Brain stimulation response profiling

ABSTRACT

Various embodiments concern delivering electrical stimulation to the brain at a plurality of different levels of a stimulation parameter and sensing a bioelectrical response of the brain to delivery of the electrical stimulation for each of the plurality of different levels of the stimulation parameter. A suppression window of the stimulation parameter can be identified as having a suppression threshold as a lower boundary and an after-discharge threshold as an upper boundary based on the sensed bioelectrical responses. A therapy level of the stimulation parameter can be set for therapy delivery based on the suppression window. The therapy level of the stimulation parameter may be set closer to the suppression threshold than the after-discharge threshold within the suppression window. Data for hippocampal stimulation demonstrating a suppression window is presented.

This application is a continuation of U.S. patent application Ser. No.14/194,026, filed on Feb. 28, 2014, now U.S. Pat. No. 9,724,517, whichis a continuation of U.S. patent application Ser. No. 13/766,006, filedon Feb. 13, 2013, now U.S. Pat. No. 8,706,237, which claims the benefitof U.S. Provisional Patent Application Ser. No. 61/600,697, filed Feb.19, 2012, and U.S. Provisional Patent Application Ser. No. 61/732,016,filed Nov. 30, 2012. The entire content of each of these applications isincorporated herein by reference.

TECHNICAL FIELD

The disclosure relates to medical devices and, more particularly, tomedical devices for therapeutic brain stimulation.

BACKGROUND

Implantable medical devices, such as electrical stimulators ortherapeutic agent delivery devices, may be used in different therapeuticapplications, such as deep brain stimulation (DBS) or the delivery ofpharmaceutical agent to a target tissue site within a patient. A medicaldevice may be used to deliver therapy to a patient to treat a variety ofsymptoms or patient conditions such as chronic pain, tremor, Parkinson'sdisease, other types of movement disorders, seizure disorders (e.g.,epilepsy), obesity or mood disorders. In some therapy systems, anexternal or implantable electrical stimulator delivers electricaltherapy to a target tissue site within a patient with the aid of one ormore implanted electrodes, which may be deployed by medical leads or ona housing of the stimulator. In addition to or instead of electricalstimulation therapy, a medical device may deliver a therapeutic agent toa target tissue site within a patient with the aid of one or more fluiddelivery elements, such as a catheter or a therapeutic agent elutingpatch.

SUMMARY

Various anti-seizure therapies and other therapies can attempt tosuppress brain activity to reduce seizures or produce anothertherapeutic effect. Stimulation can cause episodes of after-discharge.The chronic trigging of after-discharge events is not regarded as atherapy goal. Rather, suppression or other change in brain state withoutan after-discharge represents a preferred effect for chronic therapydelivery. Data is shown from hippocampal stimulation showing that asuppression effect without an after-discharge was produced with a pulseparameter level above a parameter level that failed to suppressbioelectrical activity but below a pulse parameter level that caused anafter-discharge. The data demonstrates a limited range for a pulseparameter in producing a preferred therapeutic effect. As such, apreferred stimulation parameter level is bounded by the thresholds forproducing suppression and after-discharge. Specifically, a narrowparameter window for various types of stimulation therapy is bounded bya suppression threshold on the lower end and an after-dischargethreshold on the upper end. The narrow window for therapy delivery canbe profiled and used to set stimulation outputs for therapy delivery.

Various embodiments concern delivering electrical stimulation to thebrain at a plurality of different levels of a stimulation parameter andsensing a bioelectrical response of the brain to delivery of theelectrical stimulation for each of the plurality of different levels ofthe stimulation parameter. A suppression window of the stimulationparameter can be identified as having a suppression threshold as a lowerboundary and an after-discharge threshold as an upper boundary based onthe sensed bioelectrical responses. A therapy level of the stimulationparameter can be set for therapy delivery based on the suppressionwindow. The therapy level of the stimulation parameter may be set closerto the suppression threshold than the after-discharge threshold withinthe suppression window. Data for hippocampal stimulation demonstrating asuppression window is presented. Various embodiments concern implantablemedical devices for managing therapy delivery consistent with thetechniques disclosure herein.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows data plots of bioelectrical response information fromelectrical brain stimulation.

FIG. 2 is a diagram illustrating an example bioelectrical responseprofile.

FIG. 3 is a flowchart for identifying a suppression window and setting astimulation parameter.

FIG. 4 is a flowchart for identifying thresholds and deliveringstimulation.

FIG. 5 is a flowchart for detecting patient states.

FIG. 6 is a flowchart for managing therapy delivery.

FIG. 7 is a flowchart for managing delivery of a cycled therapy.

FIG. 8A is a flowchart for managing delivery of a cycled therapyaccording to a washout period.

FIG. 8B is another flowchart for managing delivery of a cycled therapyaccording to a washout period.

FIG. 9 is a conceptual diagram illustrating an example deep brainstimulation system for delivery of electrical stimulation to a brain ofa patient.

FIG. 10 is a conceptual diagram illustrating an example therapy systemfor delivery of electrical stimulation to a brain of a patient.

DETAILED DESCRIPTION

Epilepsy and other conditions can be characterized by inappropriatebioelectrical brain activity within one or more brain structures. Forexample, some seizures associated with temporal lobe epilepsy can arisein the hippocampus of the brain. Accordingly, for at least somepatients, reducing the bioelectrical activity level within thehippocampus may reduce problematic cortical activity and may bedesirable for managing a seizure disorder. The reduced bioelectricalactivity level within the hippocampus may help mitigate symptoms of theseizure disorder, such as by lowering the likelihood of the occurrenceof a seizure, reducing the severity or duration of seizures, and/orreducing the frequency of seizures.

Deep brain stimulation is one option for therapeutically addressing aseizure disorder by lowering the activity within the hippocampus orother brain area. For example, a lead can be implanted with one or moreelectrodes contacting the hippocampus or other brain area targeted forstimulation therapy. Electrical stimulation delivered from the one ormore electrodes can change the intrinsic bioelectrical electricalactivity of the hippocampus or other targeted brain area.

One of the challenges of hippocampal deep brain stimulation for epilepsyis selection of stimulation parameters for best treatment. Currently,continuous low-voltage stimulation can be used for therapy. In somecases, therapeutic electrical stimulation of the hippocampus can bedelivered at a lower energy level relative to therapeutic electricalstimulation of the some other brain targets because of the sensitivityof the hippocampus to stimulation. The paradox is that stimulation ofthe hippocampus can cause after-discharges, which are brief seizure-likeepisodes of bioelectrical activity that occur during and/or immediatelyfollowing electrical stimulation.

Hippocampal deep brain stimulation is preferably managed for somepatients to maintain the intensity of the therapy at a level thattherapeutically addresses the seizure disorder while not causingunintended brain events. For example, some stimulation parameters mayfail to lower bioelectrical activity or otherwise therapeuticallyaddress the seizure condition while some other stimulation parametersmay be associated with unintended side effects. As mentioned above,electrical stimulation at some energy levels can cause anafter-discharge in the hippocampus.

Sensing bioelectrical activity in the brain is a useful tool forcalibrating electrical stimulation parameters. For example, thebioelectrical activity of the hippocampus or other brain area can bemonitored in real-time to provide feedback on the level of reduction ofbrain activity contributing to the seizure disorder and further on theoccurrence of any unwanted stimulation side effects.

This disclosure presents, among other things, a demonstration ofdifferent therapy levels in an ovine model and algorithms for therapymanagement. Various embodiments are presented for identifying a windowof a stimulation parameter between a minimum therapeutic threshold and aminimum threshold for unwanted provocation from the stimulation. Variousembodiments concern monitoring bioelectrical activity to set stimulationtherapy parameter levels to maintain suppression of bioelectricalactivity or otherwise cause a change in a brain state while avoidingafter-discharge events. The target locations for sensing and/orstimulation can be the hippocampus, as demonstrated herein, or othertargets within the brain. These and other aspects of therapy managementare discussed herein.

As mentioned previously, the hippocampus is an interesting target in thebrain for because of the role of the hippocampus in various seizuredisorders. Tests were done in an ovine model to understand the sensingcapabilities of an implantable brain stimulator device (an ACTIVA™ PCimplantable neurostimulator modified for sensing, made by MEDTRONIC™,Minneapolis, Minn., USA). Monitoring of bioelectrical activity wasbenefited by the ability to sense bioelectrical activity and detectbrain events while electrical stimulation was being delivered. Sensingof brain signals and detecting brain events in the presence ofelectrical stimulation is discussed in commonly assigned U.S.application Ser. No. 13/589,270 filed on Aug. 20, 2012, by Carlson etal., titled METHOD AND APPARATUS FOR DETECTING A BIOMARKER IN THEPRESENCE OF ELECTRICAL STIMULATION, which is incorporated by referenceherein in its entirety.

Preceding the tests, animals were anesthetized for surgery and 1.5 TMRIs collected. Unilateral anterior thalamic and hippocampal DBS leadswere implanted using a frameless stereotactic system, and connected tothe modified neurostimulator. Trajectories for unilateral thalamic andhippocampal DBS leads were calculated based upon gross anatomicdescriptions of the ovine brain. The implanted system allowed forstimulation and recording from both leads. In particular, the implantedsystem allowed for sensing and stimulation of both the hippocampus andanterior nucleus structures. Evoked potentials and local field potential(LFP) signals were recorded by the implanted device (422 Hz samplingrate; 0.5 Hz HP, 100 Hz LP filters), downloaded, and analyzed off-line.The test results discussed herein principally concern the directstimulation and monitoring of the hippocampus by a stimulation electrodein contact with the hippocampus, however the concepts discussed hereincould be applicable to indirect stimulation and/or monitoring of thehippocampus (e.g., by an electrode within the brain but remote from thehippocampus, such as an electrode in a brain area networked to thehippocampus) as well as direct and/or indirect sensing and stimulationof other brain structures.

FIG. 1 shows a hippocampus LFP time domain signal 101 (upper chart)recorded from a lead implanted in the hippocampus. The signal 101 wasrecorded over a period of approximately 15 minutes during an awake phasefor the animal subject. The lower chart of FIG. 1 shows a correspondingspectrogram 102 for the LFP signal 101 over the same time period.

Several notable time periods are indicated on FIG. 1. No stimulation wasdelivered during first time period 110. During the first time period110, a steady level of intrinsic bioelectrical activity of the brain canbe seen in both the LFP signal 101 and the spectrogram 102. From thissteady brain activity level over the first time period 110, a baselineamount of bioelectrical activity can be established, the baselinereflecting the amount of brain activity present when the hippocampus isunaffected by stimulation. As will be shown herein, the establishment ofa baseline can be useful as a reference for comparing bioelectricalbrain activity levels affected by stimulation to assess the effect ofthe stimulation. The root mean square (RMS) of the LFP signal 101 and/orthe spectral energy of the spectrogram 102 for the time period 110 canbe used to measure the baseline bioelectrical activity level, amongother techniques.

During the period of collection of the LFP signal 101, three groups ofstimulation pulses were delivered to the hippocampus through thehippocampal lead in three different bursts of stimulation. The pulseswithin each group were delivered at 50 Hz. A different pulse amplitudewas used for the pulses of each group of stimulation pulses. The firstgroup 120 of stimulation pulses had an amplitude of 0.5 volts. Thedominant artifact of the first group 120 of stimulation pulses isreflected in both the LFP signal 101 and the spectrogram 102 atapproximately 300 seconds.

The second time period 111 immediately follows the delivery of the firstgroup 120 of stimulation pulses. No stimulation was delivered during thesecond time period 111. As shown in both the LFP signal 101 and thespectrogram 102, the level of hippocampal activity during the secondtime period 111 is essentially the same as the level of hippocampalactivity during first time period 110 associated with no stimulation. Assuch, hippocampal brain activity was unchanged from the unstimulatedbaseline level following the first group of 0.5 volt stimulation pulsesand the amplitude of the first group 120 of stimulation pulses of thetest was sub-threshold for any effect.

At about 440 seconds into the test, a second group 121 of stimulationpulses was delivered at 50 Hz and 0.9 volts. As with the other groups ofpulses, the dominant artifact of the second group 121 of stimulationpulses is shown by both the LFP signal 101 and the spectrogram 102. Thethird time period 112 immediately follows the second group 121 ofstimulation pulses. No stimulation was delivered during the third timeperiod 112. As shown in both the LFP signal 101 and the spectrogram 102,the level of hippocampal activity during the third time period 112 (i.e.following the second group 121 of stimulation pulses) was lower relativeto the first time period 110 and the second time period 111. Inparticular, following the delivery of higher amplitude stimulationpulses (the second group 121 at 0.9 volts), the hippocampal LFP activitydecreased in amplitude and across all measured frequencies relative tobaseline hippocampal LFP activity unassociated with stimulated (firsttime period 110) and relative to hippocampal LFP activity associatedwith lower amplitude stimulation (the first group 120 at 0.5 voltsimmediately preceding second time period 111). Based on this pattern,and as discussed further herein, it is concluded that the second group121 of stimulation pulses suppressed the hippocampal LFP activity forsome time following the stimulation. In this way, the increase instimulation amplitude from 0.5 to 0.9 volts crossed a suppressionthreshold, where the lower amplitude first group 120 of stimulationpulses failed to suppress the bioelectrical activity of the hippocampusbut the high amplitude second group 121 of stimulation pulses resultedin an immediate suppression of LFP activity in the hippocampus.

It is noted that the suppression of the third time period 112 ischaracterized by a consistent reduction in the amplitude of the LFPsignal 101 and a consistent reduction in the spectral energy across allmeasured frequencies of the spectrogram 102 relative to the baselinelevels of the first time period 110, which are both sustained for over aminute. These characteristics can be used for the detection of thesuppression effect, as discussed herein.

The data of FIG. 1 further demonstrates the test results from increasingpulse amplitude and recording the bioelectrical response. A third group122 of stimulation pulses was delivered at about 580 seconds. The pulseamplitude of the third group 122 of stimulation pulses was 1.3 volts.The fourth time period 113 immediately follows the third group 122 ofstimulation pulses. No stimulation was delivered during the fourth timeperiod 113. As shown in both the LFP signal 101 and the spectrogram 102during the fourth time period 113, a significant increase in hippocampalbioelectrical activity was recorded following the third group 122 ofstimulation pulses relative to the baseline bioelectrical activity ofthe time period 110, the bioelectrical activity of second time period111 associated with ineffectual stimulation, and suppressedbioelectrical activity level of the third time period 112. Thebioelectrical response pattern of the fourth time period 113 isconsistent with an after-discharge episode, which can be detected as anepileptiform-like surge of neurological activity in response tostimulation. As shown in FIG. 1, the after-discharge is characterized bya sharp increase in the amplitude of the LFP signal 101 and an increasein the spectral energy across all measured frequencies of thespectrogram 102, which are both sustained for over ten seconds. Thesecharacteristics can be used for detection of after-discharge episodes,as discussed herein.

The after-discharge event of the fourth time period 113 lasts for aboutthirty seconds, during which time the animal exhibited a clinicalorienting behavioral response. The significantly increased bioelectricalactivity of the after-discharge event subsided by the fifth time period114. The fifth time period 114 shows hippocampal bioelectrical activitybelow the baseline level of the first time period 110. The decreasedhippocampal activity during fifth time period 114 is believed to besimilar to postictal quieting and accordingly is of a different naturethan the suppression of the third time period 112. Following theafter-discharge episode of the fourth time period 113, bioelectricalbrain activity remained suppressed for the fifth time period 114.

The tests indicate the appearance of local hippocampus suppression atstimulus levels just below the threshold for after-discharge generation.This inhibition of local activity persisted for some time after thestimulation ended, and then dissipated as LFP activity returned towardbaseline. This suppression was reproducible and could be obtained withina narrow window of stimulation parameter levels that weresupra-threshold for the suppression effect, but sub-threshold forafter-discharge generation. The demonstration of prolonged, localhippocampus suppression at relatively low stimulus levels in the awakeanimal just below the after-discharge threshold provides a basis forstimulation level titration to treat temporal lobe epilepsy, among otherconditions, as further discussed herein.

The tests demonstrates that along an increasing stimulation energyspectrum, the range of stimulation outputs that produce suppression inthe hippocampus is just below the after-discharge threshold, as shown inFIG. 1. As such, a scan of an increasing or decreasing energy parameter(e.g., pulse amplitude, width, current, and/or frequency) can reveal aminimum suppression threshold (below which significant suppression isnot observed), a stimulation parameter window within which stimulationparameters suppress bioelectrical activity, and an after-dischargethreshold, above which after-discharges are provoked by stimulation.

Various anti-seizure therapies and other therapies can attempt tosuppress brain activity to reduce seizures. However, the chronictriggering of after-discharge events is not regarded as a therapy goal.Rather, suppression or other change in brain state without anafter-discharge, as demonstrated with the second group 121 ofstimulation pulses and the subsequent third time period 112 ofsuppressed bioelectrical activity, represents a preferred effect forchronic therapy delivery. Being that the suppression effect without anafter-discharge was produced with a pulse parameter level above theparameter level that failed to suppress bioelectrical activity (i.e. thepulse amplitude of the first group 120) but below a pulse parameterlevel that caused an after-discharge (i.e. the pulse amplitude of thethird group 122), the test of FIG. 1 demonstrates a limited range for apulse parameter in producing a preferred therapeutic effect. Theinventors have thus discovered, among other things, that a preferredstimulation parameter level is bounded by the thresholds for producingsuppression and after-discharge. Specifically, a narrow window fortherapy delivery is bounded by a suppression threshold on the lower endand an after-discharge threshold on the upper end.

The narrow window for therapy delivery can be profiled and used to setstimulation outputs for therapy delivery. FIG. 2 shows a profile of thedata from the test of FIG. 1. It is noted that the interpolation of FIG.2 makes guesses at the finer suppression and after-discharge thresholdlevels for the sake of discussion herein, but greater sampling couldfurther pinpoint these thresholds as needed, depending on the resolutiondesired. FIG. 2 illustrates a stimulation parameter spectrum 201measured in volts. The parameter spectrum 201 has one-tenth voltincrements.

As demonstrated in the test of FIG. 1, different stimulation parameterlevels produce different bioelectrical responses. Pulse amplitudes belowthe suppression threshold fail to suppression brain activity to anacceptable degree. The no-suppression window 211 of FIG. 2 accordinglyspans from zero volts to 0.6 volts, up to a suppression threshold. Thesuppression window 212 is adjacent to each of the no-suppression window211 and the after-discharge window 213. As such, the suppression window212 is defined by the suppression threshold and the after-dischargethreshold. Stimulation using a parameter level within the suppressionwindow 212 will cause the desired suppression effect without provokingan unwanted after-discharge event. Stimulation using a parameter levelwithin the after-discharge window 213 will provoke an after-dischargeevent. The after-discharge window 213 may extend above 1.5 volts butexploring bioelectrical responses above the after-discharge window 213is outside of the scope of this disclosure.

A chart identical or similar to that of FIG. 2 can be generated anddisplayed to profile the responses of a patient along a stimulationparameter spectrum. This information can be useful to a clinician forunderstanding the unique response profile of a particular patient. Aparameter level for therapy delivery may be set based on the profile.For example, a stimulation parameter setting 230 may be selected withinthe suppression window 212 for therapy delivery. As shown in FIG. 2, thestimulation parameter setting 230 is weighted to be closer to thesuppression threshold than to the after-discharge threshold (by a ratioof 1/3) along the stimulation parameter spectrum 201. Selecting atherapy output weighted closer to the suppression threshold within thesuppression window may provide a stimulation output that reliablyproduces the suppression therapeutic effect while minimizing energy useand the likelihood of unintended stimulation. It is noted that thetechniques discussed in connection with FIGS. 1 and 2 can be implementedby control circuitry of a medical device to automatically, among otherthings, identify a suppression window and/or set a parameter level fortherapy delivery.

FIG. 2 shows that the zones of no-suppression 211, suppression window212, and after-discharge 213 are contiguous along a stimulationparameter spectrum. As such, a scan of a stimulation parameter (e.g.,pulse amplitude) along the stimulation parameter spectrum can identifythe zones, thresholds, and the suppression window for setting therapysettings. Scans along a stimulation parameter spectrum will further bediscussed in association with FIGS. 3 and 4.

FIG. 3 shows a flowchart of a method 300 for determining one or morestimulation parameters. The stimulation parameters could be used for thetreatment of epilepsy, e.g., treating seizures associated with temporallobe epilepsy with hippocampal stimulation. However, the techniques ofFIG. 3 could be applied to various other brain areas and/or diseaseconditions.

The method 300 includes delivering 310 electrical stimulation to atarget site within the brain at a plurality of different parameterlevels. The electrical stimulation can be delivered 310 in a series ofpulse groups, as in FIG. 1, where different pulse energy parameters areused between the different pulse groups. In some embodiments, thedifferent parameter levels correspond to different energy levels, suchas different pulse amplitudes, widths, frequencies (e.g., the frequencyat which pulses within a group are delivered), and/or currents betweenthe groups. In some embodiments, only one pulse parameter is variedbetween the different pulse groups (e.g., just pulse amplitude) to testthe different energy levels, while in some other embodiments multiplepulse parameters are varied between the different pulse groups. In someembodiments, a pulse parameter is incremented or decremented betweeneach pulse group. For example, a scan of different pulse voltages couldbe performed in increments of one tenth of a volt for each pulse group,the different voltages corresponding to the stimulation parameterspectrum of FIG. 2.

The method 300 also includes sensing 320 a baseline bioelectricalactivity level and a bioelectrical response to the stimulation delivery310 for each of the different levels of the stimulation parameter.Sensing 320 bioelectrical activity can include sensing LFP signals withone or more electrodes in the hippocampus, as discussed herein, or othertarget location. Sensing 320 to determine the baseline bioelectricalactivity level can be done before or after delivery 310, but in any caseis done at a time when the target brain area will be unaffected bystimulation so that a baseline bioelectrical activity level can beestablished based on intrinsic brain activity. As discussed herein,determining the baseline activity level can be used to determine whenbrain activity is suppressed due to stimulation and when it is unusuallyhigh due to stimulation (e.g. corresponding to an after-discharge).

Sensing 320 of a bioelectrical response to the stimulation delivery 320can be performed during and/or immediately following the delivery 310 ofstimulation at a respective stimulation parameter level of the pluralityof different levels of the stimulation parameter. Preferably, therespective deliveries of stimulation at the plurality of differentlevels are separated from each other in time to allow the response ofthe brain area of each delivery at a particular stimulation parameterlevel to be fully recognized free of the effects of the stimulationdelivery at the other parameter levels. It is noted that while theflowchart of the method 300 has the delivery 310 and sensing 320 stepssequentially, the steps may be performed at the same time and/orinterspaced for delivery 310 and sensing 320 for each delivery ofstimulation at a different parameter level.

Based on the sensed 320 baseline bioelectrical activity level and thebioelectrical responses for the plurality of different stimulationparameter levels, a suppression window 330 can be identified. Thesuppression window can be identified 330 as being defined by asuppression threshold as a lower boundary and an after-dischargethreshold as an upper bound along a spectrum of the stimulationparameter.

Suppression can be detected as a reduction is bioelectrical activityrelative to a baseline level (e.g., as a reduction by 25% or some otheramount) during and/or following delivery 310 of electrical stimulationat a particular parameter level. The amount of the reduction used todetect suppression may be a predetermined value or may be selected(e.g., for a particular patient) based on patient condition, diseasestate, one or more monitored parameters of the patient, and so on. Insome cases, the amount may be selected based on a database containinghistorical patient data, including data for patients having a similarcondition, disease state, and so on, as the current patient. In somecases, the value used for this amount may be dynamically adjustable.

An after-discharge can be detected as a surge in bioelectrical activityrelative to a baseline level (e.g., as a sudden increase by 25% or someother amount) during and/or immediately following delivery 310 ofelectrical stimulation at a particular parameter level. As was the casewith the value used to detect suppression, the amount used to detect anafter-discharge may be a predetermined value or may be selected (e.g.,for a particular patient) based on patient condition, disease state, oneor more monitored parameters of the patient, and so on. In some cases,the amount may be selected based on a database containing historicalpatient data, including data for patients having a similar condition,disease state, and so on, as the current patient. In some cases, thevalue used for this amount may be dynamically adjustable.

Detecting suppression and after-discharge events as well as thresholdsand windows can be performed in various manners, such as by using thetechniques discussed in connection with FIG. 4 or elsewhere herein.

Parameters for a stimulation therapy can be set 340 based on thesuppression window. According to various embodiments, the stimulationparameters are set 340 at a level within the identified 330 suppressionwindow (i.e. at a parameter level above the suppression threshold andbelow the after-discharge threshold). In some embodiments, thestimulation parameters are set 340 at a level weighted to a lowerparameter level (i.e. closer to the suppression threshold than to theafter-discharge threshold) within the identified 330 suppression window,such as at ¼ or ⅓ of the span of the window.

Multiple stimulation energy parameters can be tested in variousembodiments. For example, the method 300 of FIG. 3 (or any other methodherein) can be repeated for each of a plurality of different stimulationparameters. For example, a first scan can test stimulation amplitude asthe stimulation parameter, and a second scan can test pulse width, and athird scan can test the pulse frequency. Suppression windows can beidentified for each of the different energy parameters. Stimulationtherapy parameter levels can then be set 340 for each of the differentenergy parameters based on respective suppression windows. In someembodiments, a single scan can vary multiple different energyparameters.

In various embodiments, the scan of the method 300 (e.g., the delivery310, sensing, 320 and identification 330 steps) are performed repeatedlyfor a plurality of different electrodes (in unipolar stimulation mode)and/or electrode combinations (in bipolar stimulation mode). A preferredelectrode or electrode combination can then be selected for therapydelivery and a therapy parameter level within the suppression window ofthe selected electrode or electrode combination can be set 320. In someembodiments, the preferred electrode or electrode combination fortherapy delivery can be selected based on which electrode or electrodecombination produced the suppression window with the lowest suppressionthreshold as a lower boundary (i.e. the lowest stimulation parameterthat caused suppression) amongst multiple electrodes and/or electrodecombinations scanned (e.g., in the manner of FIG. 3). A lowersuppression threshold means that the therapy can be delivered at a lowersetting, saving power and minimizing the chances of intendedstimulation, and accordingly an electrode or electrode combination thatcan be used to deliver therapy at the lowest energy level would bepreferred relative to other electrodes and electrode combinationsassociated with higher suppression thresholds. In some embodiments, thepreferred electrode or electrode combination for therapy delivery can beselected based on which electrode or electrode combination produced thewidest suppression window (i.e. the greatest parameter range between thesuppression threshold and the after-discharge threshold). The widestsuppression window allows for the greatest range to vary a stimulationparameter, which may be useful if a user is permitted to adjust thestimulation parameter within the suppression window or a closed-looptherapy control can vary the stimulation parameter within the window.

As shown above, a method can be used to determine a profile of whichstimulation parameter(s) cause suppression without after-discharges. Theprofile can also include which stimulation parameters of differentstimulation electrode and/or electrode combinations cause suppressionand after-discharges. A scan to determine the suppression andafter-discharge thresholds is feasible because, as demonstrated in thedata discussed above, the suppression window is bounded by theafter-discharge threshold. As such, a scan of stimulation responses fromno-suppression to after-discharge can profile a window for managingtherapy delivery. In some embodiments, a report can be generated forclinician review showing the suppression and after-discharge thresholdsof a suppression window. If an implantable medical device performs thescan, then the profile can be wirelessly transmitted to an externaldevice for display. In some embodiments, the report can resemble thechart of FIG. 2.

It is noted that any and all of the steps and options discussed inconnection with FIG. 3, or otherwise discussed herein, can be performedautomatically by a medical device. For example, control circuitry of animplantable medical device may perform the steps of the method 300 ofFIG. 3 without user intervention to manage therapy delivery.

FIG. 4 shows a flowchart of a method 400 for determining stimulationparameters. The stimulation parameters could be used for the treatmentof epilepsy, such as suppressing seizures associated with temporal lobeepilepsy with hippocampal stimulation. However, the techniques of FIG. 4could be applied to various other brain areas and/or disease conditions.

The method 400 includes sensing 401 bioelectrical activity within abrain at a sense location to determine a baseline bioelectrical activitylevel. Sensing 401 bioelectrical activity can include sensing LFPsignals with one or more electrodes in the hippocampus or other locationas a sense location. Sensing 401 can be performed over a predeterminedamount of time to get a broad measure of bioelectrical activity of thesense location, such as an amount of time ranging from between 30seconds and 10 minutes. Examples include fifty seconds or five minutes,although other time periods are contemplated. In various embodiments, nostimulation is delivered during sensing 401 so that a baseline can bedetermined without the influence of stimulation.

Stability check 402 can be performed to determine whether the sensed 401bioelectrical activity is stable. In various embodiments, thebioelectrical activity is stable when the RMS or energy (e.g., spectralenergy within a particular frequency band) of the LFP signal does notdeviate by a threshold amount (e.g., 10% or other predetermine amountfrom the RMS or energy level) for a predetermined amount of time, amongother techniques for assessing bioelectrical activity stabilization of abrain area. Once the bioelectrical activity is stable, then a baselinebioelectrical activity level can be set 403. If variation in thebioelectrical activity prevents setting 403 the baseline, then themethod 400 can continue sensing 401 bioelectrical activity and checking402 whether bioelectrical activity stabilization has occurred until abaseline can be set 403.

Once the baseline is set 403, electrical stimulation can be delivered410 to a target site within the brain. The target site may be the samebrain area as the sense location, such as the hippocampus. However, invarious embodiments, the sense location and target site for stimulationare different areas of the brain that are networked. In someembodiments, the target site will correspond to an electrode orelectrode combination used for stimulation, such that different targetsites are stimulated by different electrodes or electrode combinations.In some examples, multiple sites may be selected for stimulation and/ormultiple sites may be selected for sensing. One or more of the multiplesites used for sensing may, but need not, be the same sites used fordelivery of the stimulation. Delivery 410 of the electrical stimulationmay comprise delivery of a group of pulses as referenced herein, such asa brief series of pulses output using particular energy parameters,e.g., amplitude, current, width, and frequency of pulses within thegroup.

At the same time as the delivery 410 of electrical stimulation, and/orfollowing the delivery 410 of electrical stimulation, bioelectricalactivity is sensed 420 within the brain at the sense location. Asdiscussed herein, electrical stimulation can have a suppressive effecton electrical brain activity, which can be associated with a lowerincidence of seizure or other therapeutic benefit. As such, sensing 420can be performed to determine whether bioelectrical activity hasdecreased from the baseline in association with delivery 410 of theelectrical stimulation.

Suppression check 425 can determine whether the bioelectrical activitylevel has decreased from the previously set 403 baseline. Brain activitysuppression from stimulation can be identified in various ways, asdiscussed herein. Depending on how the baseline is measured (e.g., RMS,signal energy), a 20% decrease in the measure of brain activity from thebaseline during sensing 420 could indicate suppression due to thedelivery of electrical stimulation 410. The amount of the decrease usedto detect suppression may be selected, in some cases, based onhistorical patient data gathered from other patients having a same orsimilar condition and/or disease state. Depending on the predeterminedamount of change from baseline (e.g., 20%, 50%, or other amount) fordetection, suppression check 425 can be passed if sufficient suppressionis identified. If the predetermined amount of change from baseline isnot detected during and/or following delivery 410 of electricalstimulation, then the method 400 can change 430 a stimulation parameterand then continue delivering 410 electrical stimulation with the changedparameter.

In various embodiments, changing 430 a stimulation parameter willcomprise increasing a stimulation energy parameter in an effort to bringabout the suppression. Energy parameters can include pulse amplitude(e.g., current or voltage), width, and frequency, among otherparameters. In this way, repeated failure to sense 420 a signal having acharacteristic of a suppression effect produced through stimulationdelivery 410, as verified by suppression check 425, causes repeatedincreasing of stimulation energy by changing 430 the stimulationparameter in an incremental manner until a stimulation energy level isreached that suppresses bioelectrical activity in the target area.Although this example concerns an incrementing energy level change,other manners of changing 430 a stimulation parameter could be used,such as a decrementing change in a downward scan.

In some embodiments, suppression check 425 must confirm a sustainedsuppression to be passed, such as determining whether the suppression ofbioelectrical activity persists for a predetermined about of time(during and/or following delivery 410 of electrical stimulation), suchas ten seconds, one minute, or some other amount of time.

Upon the recognition of suppression of the bioelectrical activity in thebrain area by suppression check 425, a suppression threshold can be set440. The suppression threshold 440 can be set based on theidentification of a stimulation setting that produces a suppressioneffect of bioelectrical activity after changing 430 a stimulationparameter from a level that failed to pass the suppression check 425.The suppression threshold can be set 440 at the lowest level of astimulation parameter (e.g., amplitude, pulse width, frequency, or otherenergy parameter) that produces a suppressive effect in the targetedbrain area. For example, if a scan as described above was incrementingpulse voltage by a tenth of a volt for each change 430 in a stimulationparameter, and suppression was recognized by suppression check 425following the delivery 410 using 1.4 volts but not using 1.3 volts, then1.4 volts may be selected as the suppression threshold. In some casesthe suppression threshold is set 425 at some amount above the loweststimulation parameter that produced the suppression effect to provide amargin of safety, such as in cases where therapy parameters are laterset at or very close to the suppression threshold.

While the steps of delivering stimulation 410, sensing 420, checking425, and changing 430 can be repeated in a loop to scan a parameterrange for a suppression threshold, further steps in the method 400 cancontinue the scan to identify other notable aspects of a patient'sresponse to different stimulation outputs. The method 400 can continuewith the scan with the same output parameters that produced thesuppression effect. Delivering 450 electrical stimulation and sensing460 bioelectrical activity at the same time as stimulation delivery 450and/or following deliver 450 can be done in the same manner asdelivering 410 electrical stimulation and sensing 420 bioelectricalactivity, except that the sensed 460 bioelectrical signal(s) areanalyzed for evidence of an after-discharge episode for theafter-discharge check 465.

It is unlikely that the same parameters that previously produced thesuppression effect are also going to cause an after-charge in the scan,per the after-discharge check 465, and in which case the stimulationparameters can be changed 470. The change 470 in stimulation parameterscan be an increase in stimulation energy, such as an increment in astimulation parameter (e.g., pulse or waveform amplitude, width,frequency, or other energy parameter). In some embodiments, thestimulation parameter change 430 and 470 steps implement the samechange, such as a pulse amplitude increment of the same amount, while inother embodiments the steps implement different parameter changes.

The loop of the steps of delivering 450 electrical stimulation, sensing460 bioelectrical activity, monitoring for after-charge atafter-discharge check 465, and changing 470 a stimulation parameter canbe repeated in a loop until an after-discharge episode is detected,passing after-discharge check 465. An after-discharge threshold can thenbe set 480 based on the identification of a stimulation setting thatproduces an after-discharge after changing 470 a stimulation parameterfrom a level that failed to pass the after-discharge check 425. Theafter-discharge threshold can be set 480 at the lowest stimulationparameter level that first produced an after-discharge episode. In somecases, the after-discharge threshold can be set 470 at an amount belowthe lowest stimulation parameter level that first produced theafter-discharge effect to provide for a margin of safety, in case atherapy parameter is set to actively use the after-discharge threshold(e.g., as an upper-bound of a closed loop algorithm or as an upperstimulation limit on a user control).

Based on the suppression threshold being set 440 and the after-dischargethreshold being set 480, a suppression window can be identified, withthe lower bound being the suppression threshold and the upper boundbeing the after-discharge threshold. The suppression window representsthe range of a stimulation parameter that can produce the therapeuticsuppression effect without triggering an after-discharge. Thesuppression window can be used for setting therapy parameters, and insome cases can define a range within which an algorithm or user canactively change a stimulation parameter.

The method 400 further includes delivering 490 stimulation therapy tothe patient using a stimulation parameter at or above the suppressionthreshold and below the after-discharge threshold. In some embodiments,a clinician or circuitry can select a particular parameter level withinthe suppression window, such as a stimulation parameter level midwaybetween the suppression threshold and the after-discharge threshold, fortherapy delivery. In some embodiments, the selected parameter level isweighted to be closer to the suppression threshold than theafter-discharge threshold along the parameter spectrum, such as onefirth, one quarter, or one third of the way between the suppressionthreshold than the after-discharge threshold.

It is noted that therapy delivery 490 can comprise pulses delivered at80 Hz or greater, and 100 Hz or greater, and 80-140 Hz in someembodiments, however not all embodiments are so limited, as pulses canbe delivered at higher and lower frequencies.

Multiple stimulation energy parameters can be tested in variousembodiments. For example, the method 400 of FIG. 4 (or any other methodherein) can be repeated for each of a plurality of different stimulationparameters. For example, a first scan can test stimulation amplitude asthe stimulation parameter, and a second scan can test pulse width, and athird scan can test the pulse frequency. Suppression and after-dischargethresholds can be identified for each of the different energyparameters. Therapeutic stimulation can then be delivered 490 to thetarget location based on the respective suppression and after-dischargethresholds. In some embodiments, a single scan can vary multipledifferent energy parameters.

In various embodiments, the scan of the method 400 to set the 440suppression threshold and set 480 the after-discharge threshold areperformed repeatedly for a plurality of different electrodes (inunipolar stimulation mode) and/or electrode combinations (in bipolarstimulation mode). A preferred electrode or electrode combination canthen be selected, and an energy level above the suppression thresholdyet below the after-discharge threshold, can be selected for therapydelivery 490 using the selected electrode or electrode combination.Electrode or electrode combination selection can be done in any manner,such as any manner described herein.

It is noted that any and all of the steps and options discussed inconnection with FIG. 4, or otherwise discussed herein, can be performedautomatically by a medical device. For example, control circuitry of animplantable medical device may perform the steps of the method 400 ofFIG. 4 without user intervention. In some cases, some or all of thesteps may be performed by an external device or an external deviceoperating in cooperation with an implantable medical device.

It is noted that the methods 300 and 400 can correspond to the sameembodiments, with the flowcharts and discussions of FIGS. 3 and 4highlighting different aspects of parameter selection. It is also notedthat not all embodiments will perform each of the steps of the methodspresented herein, and modifications to the methods are contemplated,whether by omitting and/or adding steps. Each of the methods discussedherein can be fully or partially implemented in control circuitry of animplantable medical device (e.g., a neurostimulator configured for DBS)and/or an external device.

Various embodiments of this disclosure identify suppression andafter-discharge thresholds. A suppression threshold can be identified invarious different ways. Similarly, an after-discharge threshold can beidentified in various different ways. For example, a suppressionthreshold may be identified based on the greatest pulse parameter levelthat did not cause suppression of the brain area out of a plurality ofdifferent pulse parameter levels or the lowest pulse parameter levelthat did cause suppression of the brain area out of a plurality ofdifferent pulse parameter levels. In various embodiments, anafter-discharge threshold may be identified based on the greatest pulseparameter level that did not cause an after-discharge event out of aplurality of different pulse parameter levels or the lowest pulseparameter level that did cause an after-discharge event out of aplurality of different pulse parameter levels. It is noted that theidentification of a suppression threshold or an after-dischargethreshold does not necessarily mean determining the exact parameterlevel to the finest resolution possible, but rather can includerecognizing the relevant stimulation effects on both sides of thethreshold from a plurality of different pulse parameter levels whilechanging the stimulation parameter. For example, a suppression thresholdcan be isolated by delivering electrical stimulation at a firstparameter setting and failing to get a suppression effect, increasingthe stimulation energy to a second parameter setting, and recognizingthe suppression effect from delivery of electrical stimulation at thesecond parameter setting. Furthermore, the after-discharge threshold canbe isolated by increasing the stimulation energy to a third parametersetting and then further to a fourth parameter setting and recognizingthe suppression effect from delivery of electrical stimulation at thethird parameter setting and the after-discharge effect from delivery ofelectrical stimulation at the fourth parameter setting.

In some embodiments, the suppression caused by electrical stimulationwill reduce bioelectrical activity across all brain frequencies as inFIG. 1, or substantially all brain frequencies. In some embodiments, thesuppression caused by electrical stimulation will reduce bioelectricalactivity in a particular frequency band associated with a neurologicalcondition, such as the beta band, which may be therapeutic for variousmovement disorders. Suppression may be a reduction effect onbioelectrical activity in various embodiments, where the reductioneffect does not necessarily decrease all or a substantial amount ofbrain activity, but rather reduces some aspect of bioelectrical activityassociated with a problematic or neurological condition. For example,electrical stimulation can be delivered to reduce particular patternsassociated with a neurological condition but not reduce allbioelectrical activity of the targeted area. The reduction effect mightbe a reduction in the amplitude, energy level, or another measure ofintrinsic bioelectrical activity of the targeted brain area.

In various embodiments, control circuitry determines the level of brainactivity of a brain area based on at least one characteristic of thebioelectrical brain signal, which can be a time domain characteristic.For example, the level of bioelectrical activity of brain area can beindicated by the average, peak-to-peak, peak, median, lowest amplitude,or instantaneous amplitude of a bioelectrical brain signal sensed withinthe brain area over a predetermined period of time (e.g., the averageamplitude over about one second to about five minutes following thedelivery of stimulation to the hippocampus) or the peak-to-peakvariability of the bioelectrical signal. As other options, the level ofbrain activity of a brain area can be indicated by the variance betweenthe instant, median, or mean amplitude of a bioelectrical signal overtime, where the variance may be between subsequent slots of time orbetween a sensed bioelectrical brain signal and a stored average, peak,mean or instantaneous of the amplitude determined based on somepredetermined period of time.

In various embodiments, control circuitry may determine the level ofbioelectrical activity of a brain area based on a frequency domaincharacteristic of a bioelectrical signal sensed from the brain area.Examples of a frequency domain characteristic include, but are notlimited to, a power level in one or more frequency bands of abioelectrical signal sensed over a predetermined period of time or aratio of power levels in at least two frequency bands of thebioelectrical brain signal. The frequency domain characteristic can bedetermined based on, for example, a spectral analysis of a bioelectricalbrain signal. The spectral analysis may indicate the distribution overfrequency of the power contained in a signal, based on a finite set ofdata. In various embodiments, the frequency domain characteristic maycomprise a relative power level in a particular frequency band or aplurality of frequency bands. While “power levels” or “energy levels”within a selected frequency band of a sensed bioelectrical brain signalare generally referred to herein, the power or energy level may be arelative power or energy level. A relative power or energy level mayinclude a ratio of a power level in a selected frequency band of asensed brain signal to the overall power of the sensed brain signal. Thepower or energy level in the selected frequency band may be determinedusing any suitable technique. In some examples, control circuitry mayaverage the power or energy level of the selected frequency band of asensed brain signal over a predetermined time period, such as about tenseconds to about two minutes, although other time ranges are alsocontemplated. In other examples, the selected frequency band power orenergy level may be a median level over a predetermined range of time,such as about ten seconds to about two minutes. The activity within theselected frequency band of a bioelectrical signal sensed from a brainarea, as well as other frequency bands of interest, may fluctuate overtime. Thus, the power or energy level in the selected frequency band atone instant in time may not provide an accurate and precise indicationof the energy of the bioelectrical signal in the selected frequencyband. Averaging or otherwise monitoring the power or energy level in theselected frequency band over time may help capture a range of levels,and, therefore, a better indication of the state of the brain area.

The overall power or energy of a sensed bioelectrical brain signal maybe determined using any suitable technique. Control circuitry maydetermine an overall power or energy level of a sensed bioelectricalbrain signal based on the total level of a swept spectrum of thebioelectrical signal. To generate the swept spectrum, a processor maycontrol a sensing module to tune to consecutive frequency bands overtime, and the processor may assemble a pseudo-spectrogram of the sensedbioelectrical signal based on the power or energy level in each of theextracted frequency bands. The pseudo-spectrogram may be indicative ofthe energy of the frequency content of the bioelectrical signal within aparticular window of time.

In some cases, the baseline brain activity level may represent anintrinsic patient condition that is undesirable (e.g., a brain state inwhich one or more symptoms associated with the patient disorder to betreated via therapy are observed or a brain state in which an unwantedevent is likely to occur). Control circuitry may identify one or morecharacteristics of a sensed bioelectrical brain signal and store theidentified characteristic(s) as indicators of the baseline brainactivity level. For example, the baseline brain activity level of abrain area can be indicated by the average, peak-to-peak, peak, mean orinstantaneous amplitude of a bioelectrical signal sensed from the brainarea (e.g., the hippocampus) over a predetermined period of time (e.g.,the average amplitude over a period of time of about five seconds toabout five minutes), the variability of the bioelectrical brain signalover time, a frequency domain characteristic (e.g., a relative power orenergy in a particular frequency band or a ratio of power or energylevels), or a variability of one or more frequency domaincharacteristics (e.g., the average, peak, mean or instantaneous energylevel within a selected frequency band over predetermined period oftime) over time, among other options. A change in the level ofbioelectrical activity from the baseline in a brain area associated withthe delivery of stimulation to the area (or a different but functionallyconnected brain area) characterizing a suppression effect can be apercentage change of the bioelectrical activity level relative to thebaseline bioelectrical activity level, a gross value indicative of thechange in the bioelectrical activity level relative to the baselinebrain activity level, or any combination thereof. For example, if thelevel of brain activity in the hippocampus is indicated by an amplitudeof a bioelectrical brain signal, the change in the level of brainactivity in the hippocampus resulting from the delivery of stimulationto the same or different area of the brain characterizing thesuppression effect can be a predetermined difference associated with aclinical therapeutic benefit between the baseline amplitude and theamplitude of the bioelectrical signal sensed within the hippocampus overa predetermined duration of time during and/or following the delivery ofstimulation. Other parameters besides amplitude are also contemplatedfor measuring a change from a baseline level of bioelectrical activityof a brain area to characterize suppression or after-discharge. Invarious embodiments, the change in the signal relative to a baselinemust be greater than a threshold amount for control circuitry to confirma particular event or brain state, such as an after-discharge orsuppression.

The techniques disclosed herein can employ a supervised machine learningalgorithm (e.g., utilizing a support vector machine or anotherartificial neural network) to develop one or more discriminators fordetecting different brain states. The different states can correspond tostates of no suppression, suppression, and after-discharge, such as inFIG. 2. The detection of the different brain states can be automatedbased on the discriminators, such as for automatic detection by controlcircuitry.

In implementing such a supervised machine learning technique, controlcircuitry can receive a bioelectrical signal (e.g., a LFP signal sensedfrom the hippocampus) that represents multiple episodes of differentpatient states and extract characteristics from the signal. A cliniciancan review the extracted information and/or observe the patient todetermine at which times the patient had a first, second, or third brainstate. For example, a clinician can look at the data of FIG. 1 toidentify particular patient states (e.g., baseline, no suppression,suppression, and after-discharge) and annotate them accordingly. Theseclinician assessed brain state determinations can be temporallyassociated with the extracted signal characteristics. The extractedcharacteristics and brain state information can be used to generate aclassification boundary delineating a first brain state (e.g.,suppression) and a second brain state (e.g., no suppression). Aclassification boundary can also be set delineating additional patientstates, such as suppression and after-discharge brain states. Examplesof signal characteristics that can be extracted from a sensed signalinclude a morphology of the signal (e.g., amplitude, slope, frequency,peak value, trough value, or other traits of the signal), the spectralcharacteristics of the signal (e.g., frequency band power level, a ratioof power levels, and the like), and/or any other signal characteristicsreferenced herein.

The boundary can be formed in feature space using a supervised machinelearning algorithm. Feature space plots instances of samples in patternsin n-dimensional space, the dimensions being determined by the number offeatures used to describe the pattern. A feature is a characteristic ofa signal parameter (e.g., indicating suppression or after-discharge).Each feature of feature space defines an axis, such that the values of afeature vector (e.g., parameter data plotted in feature space for onebrain state instance) indicate the coordinates of a point within thefeature space. A feature vector is a vector defined by two or morefeature values indicative of respective parameters. A feature vector canbe mapped to a point within feature space based on the values of thefeatures in the feature vector. Each feature vector defines a point infeature space that a support vector machine implemented by a computingdevice can use to classify data. Each data point feature vector is aquantitative representation of the monitored feature values for a giventime slice (e.g., a short window of time) and each feature vectordefines a data point in the feature space that can be used, togetherwith other feature vectors as data points, to generate a boundary orestablish some other relationship (e.g., to be used to discriminatebetween baseline, no suppression, suppression, and after-dischargestates).

Training data can initially be used during a training phase to populatefeature space and determine a boundary based on known occurrences of thedifferent patient states. The occurrences of the different patientstates may be known because, as described above, they are evaluated by aclinician. For example, a clinician can review data of multiple episodes(e.g., representing samplings of baseline, no suppression, suppression,and after-discharge patient states) similar to that of FIG. 1. A brainstate indication may then be associated with corresponding data segmentsor signal characteristic levels (e.g., RMS, spectral energy) and inputinto a computing device.

A boundary can be set within feature space delineating the featurevectors of the different patient states. Such a process can then trainthe algorithm by setting the linear discriminate to differentiatedifferent patient states based on subsequently sensed data. Parameterinformation can be extracted from the later sensed signal and comparedto the boundary to determine whether the patient is in the first brainstate (e.g., similar to baseline with no suppression), the second brainstate (e.g., suppressed brain activity), or a third brain state (e.g.,an after-discharge episode) based on which side of the boundary orboundaries the subsequent data (e.g., in the form of a feature vector)would lie in feature space.

Training data feature values can be based on data from one particularpatient to be used in classifying future brain states for the particularpatient or for classifying future brain states of a different patient.In some cases, feature values are based on more than one patient andcould be used in classifying future brain states for one or morepatients. For instance, the feature values may be developed based ondata stored in a database for patients that may have similar conditionsand disease states as the current patient.

FIG. 5 illustrates a flow chart for a method 500 for determining aboundary that can be used in classification of a brain state and thenmonitoring the brain state of a patient. The method 500 includescollecting 510 a plurality of signals over a plurality of differentbrain states. The brain states can be baseline (no suppression),suppression, and after-discharge states, however additional oralternative brain states could be used. Collecting 510 in this mannermay be done in the same manner of the delivering 310 and sensing 320steps of FIG. 3, and/or in any other manner referenced herein.Collecting 510 can include sensing signals and storing the signals inmemory.

The method 500 further includes identify 520 baseline, suppression, andafter-discharge brain states from the plurality of different signals.The baseline, suppression, and after-discharge episodes may beidentified based on a characteristic of a LFP signal and/or spectrogram,such as in the manner discussed in connection with FIG. 1. The episodesmay be manually noted by a clinician viewing the data and making inputin a computing device or the identification of the episodes may bepartially or fully automated by control circuitry. A baseline state maybe identified based on a LFP signal and/or spectrogram not changing inthe absence of stimulation for a predetermined amount of time. A nosuppression state may be identified based on a LFP signal and/orspectrogram not changing from baseline (or changing only aninsignificant amount) during and/or following stimulation. A suppressionstate may be identified based on a LFP signal and/or spectrogram showingreduced bioelectrical activity relative to a baseline (e.g., reducedbelow baseline by a predetermined amount) during and/or followingstimulation. An after-discharge state may be identified based on a LFPsignal and/or spectrogram showing surging bioelectrical activityfollowing stimulation. For each of the episode identifications 520, thebioelectrical parameter levels sensed at that time can be noted.

Based on these bioelectrical parameter levels associated with thedifferent identified 520 brain states, control circuitry can map 530episodes of the brain states to feature space. Mapping 530 in this waycan generate a feature space plot of episodic feature vectors, with oneor more parameters being used for axes in feature space. One or moreboundaries may be determined 540 in the feature space using controlcircuitry, the boundaries delineating the baseline (no suppression),suppression, and after-discharge brain states. For example, a baseline(no suppression) brain state may be on one side of a boundary while asuppression brain state may be on the other side of the boundary, thecontrol circuitry setting the boundary in the separation space betweendifferent groupings of feature vectors of common brain states. Aboundary may be set manually by a clinician by recognizing groupings offeature vectors of common brain states and setting a boundary within theseparation between the different groupings.

Collecting 510, identify 520, mapping 530, and determining 540 comprisean initial training phase. Once the one or more boundaries aredetermined 540, the boundaries may be used in a classification phasethat can classify subsequent patient brain states based on incominginformation (e.g., brain state discrimination in real-time). Theclassification phase can include sensing 550 one or more signals duringand/or following stimulation delivery. Characteristics of the signalsmay be extracted from the sensed 550 signals in the same manner as theidentifying 520 brain states step, although the use of differentanalysis circuitry and/or techniques for the different phases iscontemplated. In any case, a current brain state of a patient may bedetermined 560 based on one or more boundaries and the one or moresignals, the boundary serving as a brain state threshold. The currentpatient state may be determined 560 by control circuitry running alinear discriminant algorithm which can determine on which side(s) ofthe one or more boundaries a current feature vector is, the currentfeature vector derived from the one or more sensed 550 signals.

An output may be generated 570 based on the determined 560 brain state.The output may be any output referenced herein, including stoppingstimulation (e.g., in the case of an after-discharge), increasingstimulation intensity (e.g., in the case of no suppression), decreasingstimulation intensity (e.g., in the case of an after-discharge),maintaining stimulation energy (e.g., in the case of confirmation ofsuppression), alerting a patient and/or clinician to the brain state,and/or storing data characterizing the brain state episode of thepatient.

In various embodiments, the training phase can be used without theclassification phase and the classification phase can be used withoutthe training phase. For example, a boundary may be set using a techniquethat is substantively different from the training phase of the method500 and that boundary may be used to classify brain state episodes.Also, the training phase may determine 540 a boundary that is used in asubstantively different way as the classification phase of the method500 to classify patient state episode or for some other purpose. It isnoted that the training phase may be performed in accordance to any oftechniques discussed in connection with FIGS. 1-4 while theclassification phase may be performed in accordance to any of techniquesdiscussed in connection with FIGS. 6-8.

Aspects of detecting various patient states and using feature space,among other things, that can be applied to the present subject matterare disclosed in commonly assigned U.S. Pat. App. No. 2010/0280335 toCarlson et al., which is entitled “PATIENT STATE DETECTION BASED ONSUPERVISED MACHINE LEARNING BASED ALGORITHM” filed Nov. 4, 2010; andU.S. Pat. App. No. 2010/0280334 to Carlson et al., which is entitled“PATIENT STATE DETECTION BASED ON SUPPORT VECTOR MACHINE BASEDALGORITHM” filed Nov. 4, 2010, which are incorporated herein byreference in their entireties.

In some embodiments, a patient or other user is allowed some controlover therapy delivery by controlling the input. For example, a patientor other user may increase or decrease therapy intensity as desired bycontrolling the input (e.g., a switch, button, dial, or other control),but the system will not allow the stimulation parameters to be adjusted(e.g., without specific clinician intervention to override thelimitation) to a level outside of the suppression window. In someembodiments, a patient or other user is allowed to adjust stimulationintensity but is not allowed to increase stimulation intensity in amanner that would increase a stimulation parameter above theafter-discharge threshold. In some embodiments, a closed loop algorithmis set to automatically change a stimulation parameter of a therapybased on an input. For example, the stimulation parameter may be able torange within the suppression window based on the input in someembodiments but is prevented from deviating outside of the suppressionwindow. In some embodiments, the input is based on a sensed signal, suchas a physiological signal, a neurological signal, a cardiac signal(e.g., indicative of heart rate or blood pressure), a posture signalindicative of the posture of the patient, an activity signal indicativeof the activity of the patient (e.g. an accelerometer signal indicativeof patient movement), or some other signal. The suppression window orthreshold used to limit user or automatic therapy adjustment based on aninput may be set using any technique herein, such as any of FIGS. 3-5for example.

FIG. 6 is a flowchart of a method 600 for controlling a therapy based ondetection of suppression and after-discharges. The method 600 canconcern embodiments operating according to a closed loop algorithm forcontrolling a chronic therapy. The therapy may comprise the delivery ofa continuous therapeutic signal or train of pulses, monitoring of thebioelectrical response to the stimulation, and changing a stimulationparameter of the stimulation in real-time based on various bioelectricalresponses. It is noted that the method 600 can be applied to cycledtherapy embodiments where stimulation is cycled on and off according toa duty cycle. Cycled therapy embodiments will be specifically discussedin greater detail in connection with FIGS. 7 and 8.

The method 600 includes delivering 610 electrical stimulation to a brainarea, which can be a hippocampus or other brain area. The electricalstimulation can be delivered 610 in any manner referenced herein. Themethod 600 includes sensing 610 bioelectrical activity of a brain area(e.g., hippocampus), which can be done in any manner referenced herein,and can further be done simultaneously with and/or following delivery610 of the electrical stimulation.

Based on the sensed 610 bioelectrical activity, after-discharge check625 and suppression check 635 can be performed. In this way, one or morealgorithms can be run using a monitored bioelectrical signal to detectsuppression and after-discharge events. Such checks may be performedperiodically (e.g., every one minute or other interval), constantly, orperformed in response to an event (e.g., an accelerometer or othersensor indicating the occurrence of a seizure or other event). Thesuppression detection can be performed by any technique referencedherein. In some embodiments, the suppression detection can be performedby comparing a current signal parameter level (e.g., RMS, spectralenergy, or other parameter) to a baseline (e.g., a baseline previouslyset for the patient as discussed herein), where suppression is confirmedas long as the signal parameter is, one example, some predeterminedamount or percentage below the baseline, as may be required for somepredetermined period of time (e.g., 30% below the baseline level for tenseconds). In some other examples, the check 635 may instead compare themonitored bioelectrical signal to a predetermined fixed level ratherthan a relative level that is relative to a baseline.

The after-discharge check 625 can be performed by any techniquereferenced herein for detecting an after-discharge event. In someembodiments, the after-discharge detection can be performed by comparinga current bioelectrical signal parameter level to baseline, where anafter-discharge is detected if the signal parameter is a predeterminedamount or percentage greater than the baseline for a predeterminedperiod of time (e.g., 30% above the baseline LFP level for ten seconds).

If an after-discharge event is detected by after-discharge check 625,then stimulation is stopped (if it is being delivered). In some cases,the triggering of an after-discharge will suspend therapy delivery and anotification will be issued by an external programmer warning of thecondition. The indication of the after-discharge may have to becommunicated from an implantable device to an external device if theimplanted device performs the after-discharge detection. In someembodiments, stimulation delivery 610 will only be resumed if aclinician provides an input re-enabling therapy. In some otherembodiments, stimulation will be resumed at a decreased stimulationenergy level following detection of an after-discharge, such as bydecrementing a stimulation energy parameter, such as pulse amplitude,width, frequency, or other energy parameter. In some cases, thestimulation delivery 610 will only resume after the after-dischargeevent is confirmed to have subsided. If an after-discharge event is notdetected, then stimulation delivery 610 can continue (or resumed at thenext cycle if after-discharge check 625 is performed at the end of adelivery 610 cycle).

A suppression check 635 can also be performed. If suppression isconfirmed by suppression check 635, then delivery 610 of the electricalstimulation can continue (or resume at the next cycle if suppressioncheck 635 is performed at the end of a delivery 610 cycle). Ifsuppression is lost as confirmed by check 635, then the method 600 canincrease a stimulation energy parameter, such as by incrementing astimulation output parameter, such as pulse amplitude, width, frequency,or other energy parameter. The step of increasing 630 the stimulationmay be performed incrementally, such that each repeated failure todetect suppression at suppression check 635 causes another incrementalincrease 630 in a stimulation parameter in a looping fashion. In thisway, if suppression is lost, then it can be regained by scanning aparameter range (typically with an increasing stimulation energy level)until suppression is regained as confirmed by suppression check 635 oran after-discharge is provoked as confirmed by after-discharge check 625(in which can an alert message may be output that a suitable stimulationparameters level cannot be resolved).

While the after-discharge check 625 and the suppression check 635 areillustrated as different stages, they could be part of the samedetection algorithm or they may otherwise be performed simultaneously.In some embodiments, a suppression window may already be established(e.g., by the techniques of FIGS. 3-5) and the algorithm of FIG. 6 canchange the stimulation parameter within the suppression window bydecreasing 630 and increasing 640 a stimulation energy parameter asnecessary, but the stimulation parameter will not be changed out of theoriginally set suppression window. In some other embodiments, thealgorithm of FIG. 6, or a similar algorithm based on real-time detectionof suppression and after-discharge, can be used to automatically titrateone or more stimulation parameters without regard to a previously setsuppression window. In some embodiments, the method 600 of FIG. 6, orother method of this disclosure, can be combined with a closed loop oruser control algorithm, that can also change the stimulation parameterbased on an input as discussed herein. The input may be a user inputcontrolling the therapy level or a sensed signal, as discussed herein.The stimulation parameter level may then change according to the inputbut detection of an after-discharge (e.g., by after-discharge check 625)can over-ride the input to stop therapy or decrease 630 the stimulationparameter level. Likewise, the stimulation parameter level could changeaccording to the input but detection of loss of suppression (e.g., bysuppression check 635) can over-ride the input to increase 640 thestimulation parameter level. Such options are also application to theother embodiments of this disclosure.

As such, the method 600 demonstrates various options for closed loopstimulation of a brain area, such as a hippocampus. Each of the steps ofthe method 600 and the various options discussed herein can beautomatically performed by control circuitry of an implantable medicaldevice to titrate therapy delivery to therapeutically suppressbioelectrical activity while avoiding after-discharges. Activelyadapting stimulation parameters can be useful in some cases because thesuppression threshold and after-discharge threshold may change overtime, which accordingly changes the suppression window. Various factorscould potentially cause a threshold to change. Such factors can includechanges in the activation thresholds of the neurons, lead migration,changes in the properties of tissues around the lead (e.g., fibrouselectrode encapsulation), changes in brain states of the patient (e.g.,awake verses asleep states), changes in posture, disease progression,changes in a drug regimen the patient may be taking, and changes inhydration and other factors that can affect brain chemistry, among otherreasons that can alter previously established thresholds. Otherembodiments are contemplated for adapting stimulation in a closed-loopmanner.

It is noted that any and all of the steps and options discussed inconnection with FIG. 6, or otherwise discussed herein, can be performedautomatically by a medical device (unless specific user steps arespecified such as a user input therapy control). For example, controlcircuitry of an implantable medical device may perform the steps of themethod 600 of FIG. 6.

Various embodiments of this disclosure concern the delivery of a cycledtherapy, where stimulation is cyclically turned on and off, such asalternating periods of one minute of stimulation delivery (stimulationon) and one minute of no stimulation (stimulation off). In some cases,the benefits of therapy persist during the therapy-off periods in acarryover effect, which is referred to a washout period. For example, acycle of stimulation delivery may suppress hippocampal LFP activity andthe suppression may persist for a minute or more during a washoutperiod, while the suppression effect eventually subsides and thebioelectrical activity returns to the baseline. Some cycled therapyembodiments resume stimulation following the expiration of a timer,while some other embodiments monitor the level of suppression during thewashout period and resume therapy delivery when the suppression effectsubsides. Various options for cycled therapy are demonstrated in FIGS. 7and 8.

FIG. 7 illustrates a flowchart of a method 700 for controlling therapydelivery of a cycled therapy. The method 700 includes starting 702delivery of electrical stimulation, which can be performed in any mannerreferenced herein. When the delivery of electrical stimulation isstarted 702, a stim cycle timer can be started. The stim cycle timer cantime how long stimulation is being delivered for each cycle. Forexample, stimulation may be delivered for a first time period, and thennot delivered for a second time period, and the cycle may continuouslyrepeat the first and second cycles. The first time period of cycledstimulation may be one minute, ten minutes, one hour, or other period oftime. The second time period of cycled stimulation off may be oneminute, ten minutes, one hour, or other period of time. In variousembodiments, the first time period of stimulation is equal to the secondtime period of no stimulation, while in some other embodiments the timeperiods are not equal.

Check 704 monitors the stim cycle timer and when the stim cycle timerexpires the delivery of stimulation is stopped 706. Following thestopping 706 of stimulation, a bioelectrical activity is sensed 708.Sensing 708 of bioelectrical activity may be done in any mannerreferenced herein, such as sensing 708 of a LFP signal from ahippocampus. Based on the sensed 708 signal, a check 710 is performedfor the presence of an after-discharge. Detection of the after-dischargecan be done in any manner referenced herein. It is noted that theflowchart of FIG. 7 shows the sensing 708 and after-discharge check 710being performed after stimulation is stopped 706, however in variousembodiments sensing 708 and after-discharge check 710 are performedduring stimulation.

If an after-discharge is detected by after-discharge check 710, then astimulation energy parameter can be decreased 712. The stimulationenergy parameter may be decreased 712 by a small amount in a scanningmanner, or the stimulation energy parameter may be decreased 712 by alarge amount (e.g., by a whole volt or to just above a previouslyidentified suppression threshold) reflecting the desire to avoidsubsequent after-discharge events. The method 700 then waits until theoff cycle timer check 718 shows that the off cycle time has expiredbefore starting 702 delivery of the electrical stimulation with thedecreased 712 stimulation energy parameter for another cycle.

A suppression check 714 can be performed using the sensed 708bioelectrical activity signals. Suppression may be confirmed using anytechnique referenced herein. If suppression is identified, then themethod 700 waits until the off cycle timer check 718 shows that the offcycle time has expired before starting 702 delivery of the electricalstimulation with the same electrical stimulation parameters used in theprevious cycle. However, if suppression is not detected by suppressioncheck 714, then a stimulation energy parameter can be increased 716.Increasing 716 a stimulation energy parameter can be done incrementally(e.g., in 0.1 volt increments) to scan along a parameter spectrum towarda suppression threshold, as discussed herein. The method 700 then waitsuntil the off cycle timer check 718 shows that the off cycle time hasexpired before starting 702 delivery of the electrical stimulation withthe increased 716 stimulation energy parameter for another cycle.

It is noted that any and all of the steps and options discussed inconnection with FIG. 7, or otherwise discussed herein, can be performedautomatically by a medical device. For example, control circuitry of animplantable medical device may be configured to perform the steps of themethod 700 of FIG. 7.

As shown in FIG. 7, some cycled stimulation embodiments turn thedelivery of stimulation on and off according to a timing schedule.However, some other cycled stimulation embodiments adjust the timing ofthe cycle according to a washout period. For example, the suppressionlevel may be monitored during the washout period following a stimulationdelivery cycle to determine when the suppression effect subsides to somelevel, triggering the next cycle of stimulation. Only once thesuppression effect decreases and the bioelectrical brain activityincreases above a certain amount (e.g., a minimum suppression levelrepresenting the lowest acceptable amount of LFP activity or a return tobaseline or just below baseline), will the next delivery cycle bestarted. Some aspects of cycled stimulation based on a washout periodare further demonstrated in FIG. 8.

FIG. 8A illustrates a flowchart of a method 800 for controlling therapydelivery of a cycled therapy. The method 800 includes starting 802delivery of electrical stimulation, which can be performed in any mannerreferenced herein. When the delivery of electrical stimulation isstarted 802, a stim cycle timer can be started. The stim cycle timer canoperate any in manner for controlling the time of delivery of astimulation cycle, including as described above. Check 804 monitors thestim cycle timer and when the stim cycle timer expires the delivery ofstimulation is stopped 806. Following the stopping 806 of stimulation,bioelectrical activity is sensed 808. Sensing 808 of bioelectricalactivity may be done in any manner referenced herein, such as sensing808 of a LFP signal from a hippocampus. Based on the sensed 808bioelectrical, an after-discharge check 810 is performed for detectingafter-discharge. Detection of after-discharge can be done in any manner.It is noted that the flowchart of FIG. 8A shows the sensing 808 andafter-discharge check 810 being performed after stimulation is stopped806, however in various embodiments sensing 808 and after-dischargecheck 810 are also performed during stimulation.

If an after-discharge event is detected by after-discharge check 810,then a stimulation energy parameter can be decreased 812. Thestimulation energy parameter may be decreased 812 in any manner,including as described in connection with other embodiments herein(e.g., FIGS. 6 and 7). The method 800 also includes monitoring 814 forsuppression of bioelectrical activity based on the sensed 808bioelectrical activity. Monitoring 814 for suppression of bioelectricalactivity can be done in any manner, including comparing a current levelof bioelectrical activity to a minimum threshold or baseline amount. Forexample, a parameter of a sensed 808 LFP signal and/or spectrogram maybe compared to a minimum threshold representing the least amount ofsuppression deemed suitable before the stimulation cycle is resumed.When the parameter of the sensed 808 LFP signal and/or spectrogram risesabove the minimum threshold, as is expected to end the washout period,then the suppression check 816 can determine that the suppression hassubsided and the delivery of electrical stimulation can be started 802for another stimulation cycle. In some embodiments, the monitoring 814step compares the parameter of the sensed 808 LFP signal and/orspectrogram to a baseline bioelectrical activity level (associated withno stimulation as discussed herein), and when the parameter rises to thebaseline level or otherwise evidence that the brain state shows noremaining effect of the stimulation, then the suppression check 816 canbe satisfied and the delivery of electrical stimulation can be started802 for another stimulation cycle. In some cases, the suppression check816 is satisfied when the monitored 814 parameter level is within apredetermined amount of the baseline, such as 20% of the baseline, whichtriggers the start 802 of electrical stimulation delivery for anotherstimulation cycle. In these any other ways, various embodiments hereincan monitor the effects of the stimulation and turn on stimulation onlywhen necessary to manage a patient condition.

It is noted that an additional check may be performed that is similar tothe suppression check 714 and stimulation energy increase 716 of FIG. 7,where if suppression is not detected following the end of thestimulation cycle, then a stimulation energy parameter can be increased.

It is noted that any and all of the steps and options discussed inconnection with FIG. 8A, or otherwise discussed herein, can be performedautomatically by a medical device. For example, control circuitry of animplantable medical device may be configured to perform the steps of themethod 800 of FIG. 8A.

FIG. 8B illustrates a flowchart of a method 840 for controlling therapydelivery of a cycled therapy. The method 840 includes starting 842delivery of electrical stimulation, which can be performed in any mannerreferenced herein. When the delivery of electrical stimulation isstarted 842, a stim cycle timer can be started. The stim cycle timer canoperate any in manner for controlling the time of delivery of astimulation cycle, including as described above. Also at this time, astimulation ceiling level may be initiated, which indicates an upperallowable level that may be used for a stimulation energy parameter, aswill be discussed further below.

Following the starting 842 of stimulation, bioelectrical activity issensed 844. Sensing 844 of bioelectrical activity may be accomplished inany manner referenced herein, such as sensing 844 of a LFP signal from ahippocampus. Based on the sensed 844 bioelectrical signal, anafter-discharge check 846 is performed for detecting after-discharge.Detection of after-discharge can be done in any manner referencedherein.

If an after-discharge event is detected by after-discharge check 846,stimulation energy may be turned off 848. Also at this time, anoff-cycle timer may be started to control the time stimulation is turnedoff. In addition, an indication is recorded 850 that indicates that whenstimulation is once again turned on, stimulation energy is to bedecreased as a result of detecting the after-discharge event. Such anindication may be a flag that indicates stimulation is to be decreasedby a predetermined amount or by an amount that may bedynamically-selectable based on patient condition. In another example,such an indication may be a stored value for a stimulation energyparameter that will be used to control stimulation when stimulation isagain resumed. Other examples of indicating a decrease 850 in astimulation energy parameter are provided herein, including as describedin connection with, for instance, FIGS. 6 and 7.

Processing then continues to check 852, which monitors for expiration ofthe off-cycle timer. When this timer expires, bioelectrical activity issensed 854. Sensing 854 of bioelectrical activity may be done in anymanner referenced herein, such as sensing 854 of a LFP signal from ahippocampus. Based on the sensed 854 bioelectrical signal, anafter-discharge check 856 is performed for detecting after-discharge.Detection of after-discharge can be done in any manner referencedherein.

If the after discharge check 856 indicates an after discharge event isdetected, processing proceeds to turn 848 stim off (if stimulation hasnot already been turned off) and continue processing with steps 850-854in the aforementioned manner. On the other hand, if an after dischargeevent is not detected during the after discharge check 856, a check 858is performed based on the sensed bioelectrical activity to determinewhether suppression is indicated. This check may be performed in any ofthe ways discussed herein. For instance, a parameter of a sensed LFPsignal and/or spectrogram may be compared to a minimum thresholdrepresenting the least amount of suppression deemed suitable before thestimulation cycle is resumed. When the parameter of the sensed 808 LFPsignal and/or spectrogram rises above the minimum threshold, as isexpected to end the washout period, then the suppression check 858 candetermine that the suppression has subsided and the delivery ofelectrical stimulation can be started 842 for another stimulation cycle.Otherwise, if suppression has not subsided, processing continues tocheck 854, where the bioelectric activity is again sensed.

Returning now to the after discharge check 846, if an after dischargeevent is not detected during this check, a check 862 is made todetermine whether the stim cycle timer has expired. The stim cycle timerdetermines how long stimulation will be provided to the patient in theabsence of detection of an after discharge event. If the stim cycletimes has not expired, processing continues to check 846 where it isagain determined whether the patient has experienced an after dischargeevent. Processing based on the outcome of this check continues in theabove-discussed manner. If, however, the stim cycle time has expired862, processing continues to step 864 wherein stimulation is turned off.Also at this time, a stim off timer may be started to keep track of theamount of time the stimulation is turned off.

Next, another check 866 is then performed to determine whether an afterdischarge event has occurred. If so, processing continues to step 848where stimulation is turned off (if it hasn't already been turned off)and processing continues in a manner previously described. If an afterdischarge event has not occurred, check 868 is performed to determinewhether the stim off timer has expired. If not, processing returns tocheck 866 where it is again determined whether an after discharge eventoccurred so that appropriate action may be taken in the above-describedmanner.

If the off cycle timer expires as detected by check 868, processingcontinues to check 870 where it is determined whether suppression hasbeen achieved. As discussed above, suppression check 870 may determinewhether the bioelectrical activity level has decreased below somepreviously set baseline. Brain activity suppression from stimulation maybe identified in various ways. As merely one example, a 20% decrease inthe measure of brain activity from the baseline during sensing couldindicate suppression due to the delivery of electrical stimulation.Depending on the predetermined amount of change from baseline that isdesired (e.g., 20%, 50%, or other amount), suppression check 870 may bepassed if sufficient suppression is identified.

If the predetermined amount of change from baseline is not detectedduring and/or following delivery of electrical stimulation, then themethod 840 may perform a check 872 to determine whether the currentstimulation parameters are below the ceiling stimulation levels beyondwhich stimulation levels may not be increased in some examples. Suchceiling levels may be selected prior to start of method 840, forinstance. If stimulation parameter(s) are below the ceiling, anindication may be provided 874 that a stimulation energy parameter (orin some examples, multiple stimulation energy parameters) is to beincreased. Such an indication may involve, for instance, setting a flagthat indicates that when stimulation is again turned on, one or morestimulation energy parameters should be increased. In a particularembodiment, the setting of this flag may indicate that when stimulationis resumed, one or more stimulation parameters should be increased bysome amount that may be either a predetermined amount or a dynamicallydetermined amount (e.g., as may be determined by monitored bioelectricsignals). Alternatively, the indication recorded in step 874 may be theactual values for one or more stimulation parameters that will be usedwhen stimulation is again initiated. Stimulation may then be started 842according to the adjusted stimulation parameter value indicated by step874.

Returning to check 872, if the stimulation energy parameter(s) in usewhen stimulation was turned off were not below the determined ceilinglevels, a ceiling unlock 880 check may be performed to determine whethera stimulation energy parameter should be allowed to be increased beyondthe ceiling level. The outcome of the ceiling unlock 880 check may bebased on a variety of factors. In some cases, the outcome of this checkmay be patient-specific, condition-specific, or disease-state-specific.For instance, for certain patients, patient conditions, or diseasestates, it may be undesirable to allow the stimulation parameter valuesfrom being increased above the ceiling level. Such patients may, forinstance, be particularly susceptible to experiencing after dischargeevents or other adverse effects when stimulation energy parameters areincreased beyond some preset ceiling levels. In other cases, it may bebeneficial to allow stimulation parameter levels to be dynamicallyincreased even about the ceiling level after stimulation is started. Forinstance, some patients, conditions, or disease states may be associatedwith an increased ability to tolerate higher levels of stimulationenergy over time, and in such cases, it may be beneficial to increasestimulation levels above the ceiling over time. In some embodiments,rules may be associated with check 880 that indicate, for a particularpatient, disease state, condition, etc., when and by how a ceiling maybe exceeded.

If the ceiling unlock check 880 indicates the stimulation energyparameter(s) is not to be increased beyond the ceiling, processingcontinues to step 842 where stimulation is started without increasingthe stimulation energy parameter(s). However, if check 880 indicates itis beneficial to unlock the ceiling, processing continues to step 874wherein one or more stimulation energy parameters may be increased abovethe ceiling.

It is noted that any and all of the steps and options discussed inconnection with FIG. 8B, or otherwise discussed herein, can be performedautomatically by a medical device. For example, control circuitry of animplantable medical device may be configured to perform the steps of themethod 840 of FIG. 8B.

In some cases, the methods for detecting suppression and after-dischargethresholds, identifying a suppression window, and setting therapyparameters can be repeated for awake and sleep states. It is possiblethat the suppression and after-discharge thresholds, or at least whatwill be tolerated in the awake and sleep states, will be differentbetween the awake and sleep states. Therapy could be automaticallychanged between awake and sleep states, such as using therapy parametersthat are based on a first suppression window associated with an awakestate when the patient is awake and using therapy parameters that arebased on a second suppression window associated with a sleep state whenthe patient is sleep. Awake and sleep states can be automatically bedetected. Different electrode and electrode combinations could also beselected for therapy delivery, as discussed herein, for use during theawake and sleep states.

In various embodiments, multiple tests can be performed (e.g., themethods of FIGS. 3 and 4) for each of a cycled therapy regimen and acontinuous therapy regimen to determine whether either of them isassociated with a lower suppression threshold, a wider suppressionwindow, and/or less after-discharge episodes. Such tests can also beperformed for different electrode and/or electrode combinations forstimulation. A cycled or continuous therapy regimen can then be selectedfor therapy delivery based on which cycled or continuous mode (andfurther electrode or electrode combination) is associated with thelowest suppression threshold, widest suppression window, and/or lowestincidence of after-discharge episodes.

It is noted that the data presented herein concerns hippocampalstimulation and sensing. The hippocampus is a common area of seizurefocus, but other areas of the brain can also be a seizure focus. Thehippocampus can also be associated with other disease conditions.Accordingly, while the hippocampus is used to demonstrate variousembodiments of this disclosure, the scope of this disclosure and variousembodiments presented herein are not limited to sensing bioelectricalactivity of the hippocampus and/or stimulation of the hippocampus, asother brain targets can be used with the embodiments disclosed herein.

Targets for stimulation and/or sensing a bioelectrical response to thestimulation for addressing a neurological condition can be in, but arenot limited to, the cortex, including, but not limited to, the temporalcortex, occipital cortex, parietal cortex, frontal cortex, andentorhinal cortex. Targets for sensing and/or stimulation may not belimited to particular areas, but rather may be directed to functionallyconnected circuits of the brain, such along the Circuit of Papez. Theareas of the brain within the Circuit of Papez are believed to beinvolved in the generation and spread of seizure activity. The Circuitof Papez is one of the major pathways of the limbic system, and theregions of brain within the Circuit of Papez includes the anteriornucleus, internal capsule, cingulate, hippocampus, fornix, entorhinalcortex, mammillary bodies, and mammillothalamic tract. The areas of thebrain within the Circuit of Papez may be considered to be functionallyconnected, such that activity within one part of the Circuit of Papezmay affect activity within another part of the Circuit of Papez. In thisway, the delivery of stimulation to one area (e.g., the anteriornucleus) of the Circuit of Papez may affect the brain activity levelwithin another area of the Circuit of Papez (e.g., the hippocampus).

The embodiments referenced herein, including those of FIGS. 3-10, couldbe used for sensing bioelectrical activity of a first brain area todetermine a baseline level of activity of the first brain area,delivering electrical stimulation to a second brain area while sensing abioelectrical response of the first brain area to the stimulation andwhile systematically changing a stimulation parameter, and identifying asuppression window based on the bioelectrical response of the firstbrain area. The suppression window can then be used for therapydelivery. In some embodiments, the first and the second brain areas arethe same brain area (e.g., the hippocampus or other brain structure). Insome other embodiments, the first and the second brain areas are not thesame brain area. For example, the first brain area (i.e. the areatargeted for sensing) may be the anterior nucleus while the second brainarea (i.e. the area targeted for stimulation) may be the hippocampus.The first brain area (i.e. the area targeted for sensing) and the secondbrain area (i.e. the area targeted for stimulation) may each bedifferent areas of the cortex. In some embodiments, the second brainarea is stimulated by a remote lead that does not directly stimulate thesecond brain area (e.g., a lead located along the Circuit of Papez suchas in the anterior nucleus to stimulate the hippocampus as the secondbrain area) while a remote lead or a lead local to the first brain area(e.g., the hippocampus) senses a bioelectrical response to the remotestimulation of the second brain area. Based on the bioelectricalresponses, suppression and after-discharge thresholds can be determinedand a suppression window can be identified as discussed herein. Thesuppression window can then be used for therapy delivery.

While the techniques discussed herein are particularly suited fortreatment of temporal lobe epilepsy, the techniques discussed herein canbe used to address other conditions. Several disease conditions areassociated with abnormal levels of bioelectrical activity in the cortexof the brain, such as some seizure conditions. As such, multipledifferent disease conditions could potentially benefit from a therapy asdescribed herein. For example, stimulation to suppress bioelectricalactivity may be therapeutic in disease conditions associated withabnormal levels (e.g., abnormally high or erratic) of bioelectricalactivity. Moreover, suppression and after-discharges can be produced invarious brain areas, including cortical areas. As such, the embodimentsreferenced herein may be applicable to any brain stimulation therapy toreduce or otherwise change some aspect of bioelectrical activity whileavoiding after-discharges. Various embodiments referenced herein couldbe used to reduce symptoms of Alzheimer's disease or improve the memoryand/or concentration functions of a patient suffering from aneurological condition. Embodiments of this disclosure could be used totreat symptoms of movement disorders including without limitationParkinson's disease, dystonia, tremor, and akinesia. Embodiments of thisdisclosure could be used to treat symptoms of disorders includingwithout limitation depression, schizophrenia, addiction, sleepdysfunction, obsessive compulsive disorder, and obesity.

As such, control circuitry can be configured to automatically implementthe methods of FIGS. 3-8B or otherwise referenced herein to treatconditions other than seizure condition and/or target areas other thanthe hippocampus for sensing and/or stimulation.

In various embodiments, a report can be made detailing bioelectricalresponse information. Bioelectrical response information may becollected by an implanted device (e.g., an implanted device implementingthe methods of any of FIGS. 3-8), transmitted externally, and thedisplayed in a report by an external programmer or other device. Variousembodiments may store event data, such as the episodes of successfulsuppression by stimulation, failure of stimulation to suppressbioelectrical activity, and/or after-discharges. Such data may becollected while an implanted device operates according to anyembodiment, such as any of FIGS. 3-8. Metrics that can be calculated andprovided as a report based on sensed data can include, but are notlimited to, the number of stimulation cycles in which an after-dischargewas provoked, severity of after-discharges (e.g., the average RMS,spectral energy, or other parameter reflecting the bioelectricalintensity of a plurality of after-discharges), average degree ofsuppression from baseline, time spent in a suppressed state (e.g., totaltime, percentage of time, average duration of a suppression state),average of how long it takes a stimulation cycle to provoke anafter-discharge (e.g., average time from the start of stimulation untilan after-discharge is provoked), and/or number of patient seizures.

Different frequency bands are associated with different conditions, someof which are discussed herein in various examples. Generally acceptedfrequency bands are shown in Table 1:

TABLE 1 Frequency (f) Band Hertz (Hz) Frequency Information f <4 Hz δ(delta frequency band) 4 Hz □ f □ 8 Hz theta frequency band  8 Hz □ f □13 Hz α (alpha frequency band) 13 Hz □ f □ 35 Hz β (beta frequency band) 35 Hz □ f □ 100 Hz γ (gamma frequency band) 100 Hz □ f □ 200 Hz high γ(high gamma frequency band)

Although various embodiments presented herein concern the provoking ofan after-discharge to set stimulation parameters, some embodiments willonly scan a stimulation parameter to determine a baseline ofbioelectrical activity and a suppression threshold. For example, adevice may be configured to monitor bioelectrical activity until abaseline level can be identified and then a simulation parameter can beincreased while the device senses until suppression is detected. Astimulation parameter for therapy delivery can then be set at or somepredetermined amount above the suppression threshold. The therapy canthen be delivered. The device may monitor bioelectrical activity duringtherapy delivery to confirm suppression and make delivery adjustments ifsuppression is lost and/or stop therapy or decrease stimulationintensity if an after-discharge is detected (e.g., as in FIGS. 6-8).

Returning to the spectrogram 102 of FIG. 1, it is noted that apronounced band of activity in the theta frequency band persistedthroughout testing, and during other times when the subjects were awake.This theta frequency band was significantly diminished when the subjectswere not awake (e.g., during anesthetized states). The balance betweenexcitatory and inhibitory drive within this network is likely verydifferent under these two behavioral conditions. As such, detection of atheta band can be used to detect various patient states. For example, animplantable medical device could automatically detect awake states basedon theta band power above a threshold and detect non-awake states (e.g.,a sleep state) based on theta band power above a threshold. The thetaband energy could be sensed from the hippocampus via a lead in thehippocampus.

Different therapy parameters may be used for therapy delivery based onthe relative presence or absence of theta band activity. For example,different stimulation parameters can be used for awake and sleep states,as discussed above based on different suppression windows based on sleepand awake states, and a switch between awake and sleep parameters canautomatically be triggered based on theta band activity being above orbelow a threshold. However, awake and sleep state detection can beimplemented independently of these therapy changes, and could be usedalone or used to automatically implement other therapy changes based onawake and sleep states.

It is noted that this disclosure refers to embodiments for identifying asuppression window and using the suppression window for therapydelivery. Suppression might refer to abolishing or reducing a signatureof an undesirable brain state. While the data of FIG. 1 specificallyconcerns producing a stimulation effect in a subject, other therapeuticeffects could additionally or alternatively be produced while avoidingafter-discharge events. In some cases, producing a stimulation effectcould be understood as changing a brain state. As such, each referenceherein to suppression could instead reference changing a brain staterelative to a previous brain state (e.g., for which the brain state towhich the brain changed might not necessarily be suppression relative toa previous brain state). The previous brain state may be an unwantedbrain state having a bioelectrical signature and be associated with aneurological condition. Changing of the brain state by stimulation maycomprise reducing, eliminating, or otherwise changing the occurrence ofthe bioelectrical signature. In any case, the embodiments describedherein (e.g., FIGS. 3-8) could be modified to scan a stimulationparameter, identify a window for changing a brain state based on a brainstate change threshold (below which stimulation does not cause thechange and above which the change is produced) and an after-dischargethreshold, and then set a stimulation parameter for therapy based on thewindow for changing the brain state.

It is noted that not all embodiments will perform each of the steps ofthe methods presented herein, and modifications to the methods arecontemplated, whether by omitting and/or adding steps. Each of themethods discussed herein can be fully or partially implemented incontrol circuitry of an implantable medical device (e.g., aneurostimulator configured for DBS) and/or an external device. In someembodiments, control circuitry may be configured to implement multipleof the methods described herein, such as profiling a patient responseand/or setting stimulation parameters (e.g., as described in connectionwith FIGS. 1-5) and then controlling therapy delivery (e.g., asdescribed in connection with FIGS. 6-7).

FIG. 9 is a conceptual diagram illustrating an example therapy system910 that delivers electrical stimulation, senses a bioelectricalresponse to the stimulation, monitors a brain state, and/or adjuststherapy delivery to patient 912 to manage a brain condition, among otherfunctions described herein. System 910 includes implantable medicaldevice (IMD) 916, lead extension 918, one or more leads 920A and 920B(collectively “leads 920”) with respective sets of electrodes 924, 926and medical device programmer 922. IMD 916 may include monitoringcircuitry in electrical connection with the electrodes 924, 926 of leads920A and 920B, respectively.

System 910 may monitor one or more bioelectrical signals of patient 912.For example, IMD 916 may include a sensing module (e.g., sensing module944 of FIG. 10) that senses bioelectrical signals of one or more areasof brain 914. In the embodiment shown in FIG. 9, the signals may besensed by one or more electrodes 924, 926 and conducted to the sensingmodule within IMD 916 via conductors within the respective leads 920A,920B. As described in further detail below, in some embodiments, controlcircuitry of IMD 916 or another device (e.g., programmer 922) monitorsthe bioelectrical signals within brain 914 of patient 912 to identifyone or more biomarkers and determine a patient state, such as determinebaseline bioelectrical activity, identify suppression of bioelectricalactivity, identify an after-discharge episode, and/or perform the otherfunctions referenced herein including those referenced in connectionwith FIGS. 1-8. Control circuitry of IMD 916 or another device (e.g.,programmer 922) may analyze bioelectrical signals and/or other signals,identify bioelectrical responses and/or patient states, and/or controldelivery of electrical stimulation to brain 914 in a manner that treatsa brain condition of patient 912.

In some examples, the sensing module of IMD 916 may receive thebioelectrical signals from electrodes 924, 926 or other electrodespositioned to monitor bioelectrical signals of patient 912 (e.g., ifhousing 932 of IMD 916 is implanted in or proximate brain 914, anelectrode of housing 932 can be used to sense bioelectrical signalsand/or deliver stimulation to brain 914). Electrodes 924, 926 may alsobe used to deliver electrical stimulation from stimulation generator 942to target sites within brain 914 as well as to sense bioelectricalsignals within brain 914. However, IMD 916 can also use separate sensingelectrodes to sense the bioelectrical signals. In some embodiments, thesensing module of IMD 916 may sense bioelectrical signals via one ormore of the electrodes 924, 926 that are also used to deliver electricalstimulation to brain 914. In other embodiments, one or more ofelectrodes 924, 926 may be used to sense bioelectrical signals while oneor more different electrodes 924, 926 may be used to deliver electricalstimulation.

Examples of the monitored bioelectrical signals include, but are notlimited to, an EEG signal, an ECoG signal, an MEG signal, and/or a LFPsignal sensed from within or about one or more locations of brain 914.These and other signals can be used to perform various functionsreferenced herein.

As described in further detail below, IMD 916 may deliver therapy to anysuitable portion of brain 914. For example, system 910 may providetherapy to correct a brain disorder and/or manage symptoms of aneurodegenerative brain condition. Patient 912 ordinarily will be ahuman patient. In some cases, however, system 910 may be applied toother mammalian or non-mammalian non-human patients.

IMD 916 may include a module that includes a stimulation generator 942that generates and delivers electrical stimulation therapy to one ormore regions of brain 914 of patient 912 via the electrodes 924, 926 ofleads 920A and 920B, respectively. In the example shown in FIG. 9,system 910 may be referred to as deep brain stimulation system becauseIMD 916 may provide electrical stimulation therapy directly to tissuewithin brain 914, e.g., a tissue site under the dura mater of brain 914.In some other embodiments, leads 920 may be positioned to sense brainactivity and/or deliver therapy to a surface of brain 914, such as thecortical surface of brain 914, or other location in or along the patient912.

In the example shown in FIG. 9, IMD 916 may be implanted within asubcutaneous pocket below the clavicle of patient 912. In otherembodiments, IMD 916 may be implanted within other regions of patient912, such as a subcutaneous pocket in the abdomen or buttocks of patient912 or proximate the cranium of patient 912. Implanted lead extension918 is coupled to IMD 916 via a connector block (also referred to as aheader), which may include, for example, electrical contacts thatelectrically couple to respective electrical contacts on lead extension918. The electrical contacts electrically couple the electrodes 924, 926carried by leads 920 to IMD 916. Lead extension 918 traverses from theimplant site of IMD 916 within a chest cavity of patient 912, along theneck of patient 912 and through the cranium of patient 912 to accessbrain 914. Generally, IMD 916 is constructed of a biocompatible materialthat resists corrosion and degradation from bodily fluids. IMD 916 maycomprise a hermetic housing 932 to substantially enclose controlcircuitry components, such as a processor, sensing module, therapymodule, and memory. In some implementations, IMD 916 and othercomponents (e.g., leads 920) may be implanted only in the head of thepatient (e.g., under the scalp) and not in the chest and neck regions.

Electrical stimulation may be delivered to one or more areas of brain914, which may be selected based on many factors, such as the type ofpatient condition for which system 910 is implemented to manage. In somecases, leads 920 may be implanted within the right and left hemispheresof brain 914 (e.g., as illustrated in FIG. 9) while, in other examples,one or both of leads 920 may be implanted within one of the right orleft hemispheres. Other implant sites for leads 920 and IMD 916 arecontemplated. For example, in some examples, IMD 916 may be implanted onor within cranium. In addition, in some examples, leads 920 may becoupled to a single lead that is implanted within one hemisphere ofbrain 914 or implanted through both right and left hemispheres of brain914.

Leads 920 may be positioned to deliver electrical stimulation to one ormore target tissue sites within brain 914 to manage patient symptomsassociated with a disorder of patient 912. Tissue targeted forstimulation may be the same tissue that generates the monitoredbioelectrical activity (e.g., the activity which therapy attempts tosuppress). However, in some cases the tissue targeted for stimulationwill be different from the tissue which generates the bioelectricalactivity being monitored. Leads 920 may be implanted to positionelectrodes 924, 926 at desired locations of brain 914 through respectiveholes in cranium. Leads 920 may be placed at any location(s) within oralong brain 914 such that electrodes 924, 926 are capable of providingelectrical stimulation to target tissue sites of brain 914 duringtreatment and/or proximate tissue being monitored. In some embodiments,leads may be placed such that electrodes 924, 926 directly contact orare proximate tissue targeted for stimulation and/or monitoring.

In the example shown in FIG. 9, electrodes 924, 926 of leads 920 areshown as ring electrodes. Ring electrodes are typically capable ofsensing and/or delivering an electrical field to any tissue adjacent toleads 920 (e.g., in all directions away from an outer perimeter of leads920). In other examples, electrodes 924, 926 of leads 920 may havedifferent configurations. For example, electrodes 924, 926 of leads 920may have a complex electrode array geometry that is capable of producingshaped electrical fields. The complex electrode array geometry mayinclude multiple electrodes (e.g., partial ring or segmented electrodes)around the perimeter of each lead 920, rather than a ring electrode. Inthis manner, electrical brain sensing and/or electrical stimulation maybe associated with a specific direction from leads 920 (e.g., less thanthe entire outer perimeter of leads 920) to enhance direction sensingand/or therapy efficacy and reduce possible adverse side effects fromstimulating a large volume of tissue in the case of stimulation. Assuch, electrodes can be positioned to preferentially sense from one sideof a lead and to stimulate targeted tissue and avoid stimulatingnon-targeted tissue. In examples, leads 920 may have shapes other thanelongated cylinders as shown in FIG. 9. For example, leads 920 may bepaddle leads, spherical leads, bendable leads, or any other type ofshape effective in treating patient 912.

In some embodiments, outer housing 932 of IMD 916 may include one ormore stimulation and/or sensing electrodes. For example, housing 932 cancomprise an electrically conductive material that is exposed to tissueof patient 912 (e.g., the can containing circuitry being electricalconnected to sensing and/or stimulation circuitry) when IMD 916 isimplanted in patient 912, or an electrode can be attached to housing932.

In some examples, the location of the electrodes 924, 926 within brain914 can be determined based on analysis of a bioelectrical signal of thepatient sensed via one or more of the electrodes 924, 926. For example,a particular physiological structure (e.g., the amygdala) may exhibit aunique electrical signal and, thus, facilitate positioning of theelectrodes of the lead at the desired implant location throughmonitoring of the bioelectrical signal.

Leads 920 may be implanted within a desired location of brain 914 viaany suitable technique, such as through respective burr holes in a skullof patient 912 or through a common burr hole in the cranium. Leads 920may be placed at any location within brain 914 such that electrodes 924,926 of leads 920 are capable of sensing electrical activity of the brainareas and/or providing electrical stimulation to targeted tissue fortreatment.

In some embodiments, a processor of system 910 (e.g., a processor ofprogrammer 922 or IMD 916) controls delivery of electrical stimulationby activating electrical stimulation, deactivating electricalstimulation, increasing the intensity of electrical stimulation, ordecreasing the intensity of electrical stimulation delivered to brain914 to titrate electrical stimulation therapy. In this way, therapy canbe started, stopped, and/or changed by a processor in any manner andbased on any parameter or finding as discussed herein.

System 910 may also store a plurality of stimulation programs (e.g., aset of electrical stimulation parameter values). A processor of IMD 916or programmer 922 may select a stored stimulation program that defineselectrical stimulation parameter values for delivery of electricalstimulation to brain 914 based on a characterization of neuralactivation. Where IMD 916 delivers electrical stimulation in the form ofelectrical pulses, for example, the stimulation therapy may becharacterized by selected pulse parameters, such as pulse amplitude,pulse rate, and pulse width. In addition, if different electrodes areavailable for delivery of stimulation, the therapy may be furthercharacterized by different electrode combinations, which can includeselected electrodes and their respective polarities. The therapy may becharacterized by stimulation delivery settings based on a patientresponse profile, such as using stimulation parameters within asuppression window or otherwise determined by the embodiments referencedherein (e.g., as discussed in connection with FIGS. 1-8).

External programmer 922 wirelessly communicates with IMD 916 as neededto provide or retrieve information. For example, external programmer 922may receive sensed data and/or information from IMD 916, as well as sendtherapy program information to IMD 916. Programmer 922 is an externalcomputing device that the user, e.g., the clinician and/or patient 912,may use to communicate with IMD 916. For example, programmer 922 may bea clinician programmer that the clinician uses to communicate with IMD916 and program one or more therapy programs for IMD 916. Additionallyor alternatively, programmer 922 may be a patient programmer that allowspatient 912 to input information (e.g., a self-evaluated assessmentregarding symptoms and/or patient state), select programs, and/or viewand modify therapy parameters. In some embodiments, a programmer 922 candisplay a patient profile showing a suppression threshold, anafter-discharge threshold, data (e.g., the plots of FIG. 1), a responseprofile (e.g., the response profile of FIG. 2), a log of detectedevents, and/or any other information referenced herein.

Programmer 922 is a medical device that may be a hand-held computingdevice with a display viewable by the user and an interface forproviding input to programmer 922 (i.e., a user input mechanism) and/ordisplaying information received from the IMD 916. For example,programmer 922 may include a small display screen (e.g., a liquidcrystal display (LCD) or a light emitting diode (LED) display) thatpresents information to the user. In addition, programmer 922 mayinclude a touch screen display, keypad, buttons, a peripheral pointingdevice or another input mechanism that allows the user to navigatethrough the user interface of programmer 922 and provide input. A screen(not shown) of programmer 922 may be a touch screen that allows the userto provide input directly to the user interface shown on the display.The user may use a stylus or finger to provide input to the display,such as an indication that the patient is in a particular patient stateas part of a training phase as discussed herein.

In various embodiments, programmer 922 is a medical device that may be alarger workstation or a separate application within anothermulti-function device, rather than a dedicated computing device. Forexample, the multi-function device may be a notebook computer, tabletcomputer, workstation, cellular phone, personal digital assistant oranother computing device. The circuitry components of a programmerand/or other external device(s), such as equivalent circuitry to that ofFIG. 10, can be control circuitry as means for performing functions asdescribed herein (e.g., determining a bioelectrical response tostimulation and/or changing a therapy), including those described inassociation with FIGS. 1-8. Various embodiments of external circuitrymay include a screen on which information can be presented. The outputof a screen may be controlled by control circuitry.

When programmer 922 is configured for use by the clinician, programmer922 may be used to transmit initial programming information to IMD 916.This initial information may include hardware information, such as thetype of leads 920, the arrangement of electrodes 924, 926 on leads 920,the position of leads 920 within brain 914, initial programs definingtherapy parameter values, and any other information that may be usefulfor programming into IMD 916. Programmer 922 may also be capable ofcontrolling circuitry of the IMD 916 in carrying out the functionsdescribed herein.

The clinician may also store therapy programs within IMD 916 with theaid of programmer 922. During a programming session, the clinician maydetermine one or more stimulation programs that may effectively bringabout a therapeutic outcome that treats a brain condition, such with asthe therapy parameter setting techniques of FIGS. 3-5. During theprogramming session, the clinician may evaluate the efficacy of the oneor more stimulation settings (e.g., pulse amplitude, pulse width, pulsefrequency, and a resultant bioelectrical response) based on one or morefindings of a sensed signal. In some examples, programmer 922 may assistthe clinician in the creation/identification of stimulation programs byproviding a methodical system for identifying potentially effectivestimulation parameter values, such as by recommending stimulationparameters within a suppression window and/or using an electrode(s)associated with the lowest suppression threshold. In some examples, theprocessor of programmer 922 may calculate and display one or moretherapy metrics for evaluating and comparing therapy programs availablefor delivery of therapy from IMD 916 to patient.

Programmer 922 may also provide an indication to patient 912 whentherapy is being delivered which may aid the assessment of therapyefficacy. For example, concurrent with or following the delivery ofelectrical stimulation, the patient may evaluate whether he or she seemsto have symptoms (e.g., of a seizure) by answering questions presentedon the programmer 922 corresponding to times when baseline bioelectricalactivity levels are sensed, when suppression is detected, during anafter-discharge, and/or during a washout period. The information may beused to determine the relationship between stimulation intensity and abioelectrical response, such as in the training phase of FIG. 5.

Whether programmer 922 is configured for clinician or patient use,programmer 922 may be configured to communicate with IMD 916 and,optionally, another computing device, via wireless communication.Programmer 922, for example, may communicate via wireless communicationwith IMD 916 using telemetry techniques known in the art, includinginductive telemetry, arm's-length telemetry, and longer-range telemetry.Programmer 922 may also communicate with another programmer or computingdevice via a wired or wireless connection using any of a variety oflocal wireless communication techniques, such as RF communicationaccording to the 802.11 or Bluetooth specification sets, infrared (IR)communication according to the IRDA specification set, or other standardor proprietary telemetry protocols. Programmer 922 may also communicatewith other programming or computing devices via exchange of removablemedia, such as magnetic or optical disks, memory cards or memory sticks.Further, programmer 922 may communicate with IMD 916 and anotherprogrammer via remote telemetry techniques known in the art,communicating via a local area network (LAN), wide area network (WAN),public switched telephone network (PSTN), or cellular telephone network,for example.

FIG. 10 is a functional block diagram illustrating components of IMD916. In the configuration shown in FIG. 10, IMD 916 includes processor940, memory 941, stimulation generator 942, and sensing module 944,which can be control circuitry as means for performing functions asdescribed herein (e.g., delivering stimulation, sensing a brain signal,determining a bioelectrical response to the stimulation from the signal,and administering therapy based on the response and/or any of thetechniques referenced in connection with FIG. 1-8). Memory 941 mayinclude any volatile or non-volatile media, such as a random accessmemory (RAM), read only memory (ROM), non-volatile RAM (NVRAM),electrically erasable programmable ROM (EEPROM), flash memory, and thelike. Memory 941 may store computer-readable instructions that, whenexecuted by processor 940, cause IMD 916 to perform various functionsdescribed herein. Memory 941 may include operating instructions 956executable by the processor 940 for causing the IMD 916 to carry out thevarious functions referenced herein, including those discussed inassociation with FIGS. 1-8. Memory 941 may store therapy instructions aspart of stimulation programs 952 that are available to be selected byprocessor 940 in response to particular conditions (e.g., nosuppression, suppression, after-discharge) detected by the sensingmodule 944 or determination of a particular patient state. In addition,processor 940 may be configured to record diagnostic information, suchas sensed signals, measured values, detected events, biomarkersignatures, patient state episode information, and the like in memory941 or another memory or storage device. The various functions andtechniques described herein may be performable automatically by the IMD916 by processor 940 execution of operating instructions 956 andstimulation programs 952 stored in memory 941.

The steps, procedures, techniques, etc. referenced herein may be carriedout in part by, for example, software or firmware instructions, such asthose used to define a software or computer program. The non-transitorycomputer-readable medium (e.g., memory 941) may store instructions(e.g., operating instructions 956 and stimulation programs 952)executable by a processor (e.g., processor 940 and/or of an externaldevice) to carry out the steps, procedures, techniques, etc. In thisway, control circuitry can be configured to perform the various steps,procedures, techniques, etc. as described herein, including thosediscussed in association with FIGS. 1-8. The computer-readable mediummay be a computer-readable storage medium such as a storage device(e.g., a disk drive, or an optical drive), memory (e.g., a Flash memory,random access memory or RAM) or any other type of volatile ornon-volatile memory that stores processor executable instructions (e.g.,in the form of a computer program or other executable) as part ofcontrol circuitry to carry out the functions described herein.

Processor 940 may be configured to cause stimulation generator 942 todeliver electrical stimulation with pulse voltage or current amplitudes,pulse widths, and frequencies (i.e., pulse rates) as part of controlcircuitry, and electrode combinations specified by the stimulationprograms 952, e.g., as stored in memory 941. Processor 940 may controlstimulation generator 942 to deliver each pulse, or a group of pulses,according to a different program of the stimulation programs, such thatmultiple programs of stimulation are delivered on an interleaved oralternating basis, e.g., having different delays or responding todifferent biomarkers, bioelectrical responses, or patient states. Insome embodiments, processor 940 may control stimulation generator 942 todeliver a substantially continuous stimulation waveform rather thanpulsed stimulation.

As shown, the set of electrodes 924 of lead 920A includes electrodes924A, 924B, 924C, and 924D, and the set of electrodes 926 of lead 920Bincludes electrodes 926A, 926B, 926C, and 926D. Processor 940 maycontrol switch module 946 to route sensed signals to sensing module 944and/or apply the stimulation signals generated by stimulation generator942 to selected combinations of electrodes 924, 926. In particular,switch module 946 may couple stimulation signals to selected conductorswithin leads 920, which, in turn, deliver the stimulation signals acrossselected electrodes 924, 926. Switch module 946 may be a switch array,switch matrix, multiplexer, or any other type of switching moduleconfigured to selectively couple stimulation energy to selectedelectrodes 924, 926 and to selectively sense bioelectrical signals withselected electrodes 924, 926. Hence, stimulation generator 942 iscoupled to electrodes 924, 926 via switch module 946 and conductorswithin leads 920. In some embodiments, however, IMD 916 does not includeswitch module 946.

Sensing module 944 is configured to sense bioelectrical signals ofpatient 912 via a selected subset of one or more electrodes 924, 926, orwith one or more electrodes 924, 926 and at least a portion of aconductive outer housing 932 of IMD 916, an electrode on an outerhousing of IMD 916, or another reference. In some embodiments, sensingmodule 944 may measure the amplitude of a signal and relate the value toprocessor 940. Processor 940 may control switch module 946 toelectrically connect sensing module 944 to selected electrodes 924, 926.In this way, sensing module 944 may selectively sense bioelectricalsignals with different combinations of electrodes 924, 926 (and/or areference other than an electrode 924, 926). Although the electrodes924, 926 are principally described as being implanted within a brain inthe manner of DBS, other locations are additionally or alternativelycontemplated. For example, electrodes may be deployed at selected tissuesites or on selected surfaces of a human patient, such as on the brain,along the cortex, proximate the spinal cord, on the scalp, or elsewhere.As an example, scalp electrodes may be used to measure or record EEGsignals. As another example, electrodes implanted at the surface of thecortex may be used to measure or record ECoG signals. In someembodiments, an external device may be worn with sensing elementspositioned at a desired location adjacent the patient to detect abioelectrical signal.

Sensing module 944 may form part of a sensor circuit configured tomonitor a variety of signals via a variety of different sensingelements, such as a bioelectrical signal via electrodes 924, 926, and/orother physiological signals. Sensing module 944 may include amplifiers,filters, modulators, and other circuitry for conditioning and measuringone or more parameters of signals. Sensing module 944 and/or processor940 (and/or other circuitry) may condition one or more sensed signals toaccount for noise and/or identify a bioelectrical response according toany technique referenced herein. In some embodiments, sensing module 944may directly process signals obtained from electrodes 924, 926 or othersensing elements with little or no preprocessing by other components. Inother embodiments, sensing module 944 may include preprocessingcircuitry to process or convert signals for analysis by processor 940 orother circuitry. In some embodiments, sensing module 944 includescircuitry configured to measure one or more parameters of an electricalsignal, such as amplitude, and processor 940 receives an output from thetelemetry module 948 of an indication of the measurement for furtheranalysis as discussed herein, such as extracting spectralcharacteristics of the signal and/or determining a bioelectricalresponse to stimulation. Such circuitry may further discriminate whichone of a plurality of different states.

A sensing module 944 that includes a circuit architecture that directlyextracts energy in key frequency bands of a bioelectrical brain signalmay be useful for tracking the power fluctuations within the selectedfrequency bands and determining a bioelectrical response to stimulationbased on the bioelectrical brain signal. In some examples, the energy inparticular frequency band or bands of a bioelectrical signal may be usedas a parameter that serves as a feature value in a supervised learningalgorithm, such as an support vector algorithm or an support vectormachine-based classification algorithm generated based on the supportvector machine algorithm.

Stimulation generator 942, under the control of processor 940, generatesstimulation signals for delivery to patient 912 via selectedcombinations of electrodes 924, 926. Processor 940 controls stimulationgenerator 942 according to stimulation programs 952 stored in memory 941to apply particular stimulation parameter values specified by one ormore programs, such as amplitude, pulse width, timing, and pulse rate.The stimulation programs 952 may also specify the timing of stimulation,such as the timing of stimulation according to a cycled stimulationregimen. In various embodiments, stimulation generator 942 generates anddelivers stimulation signals to one or more target portions of brain 914via a select combination of electrodes 924, 926.

Although sensing module 944 is incorporated into a common housing 932with stimulation generator 942 and processor 940, in other examples,sensing module 944 is in a physically separate outer housing from outerhousing 932 of IMD 916 and communicates with processor 940 via wired orwireless communication techniques.

Telemetry module 948 supports wireless communication between IMD 916 andan external programmer 922 or another computing device under the controlof processor 940. Processor 940 of IMD 916 may receive, as updates tosensing and/or stimulation programs, information concerning the therapyprograms, thresholds, and/or values for stimulation parameters fordelivering therapy from programmer 922 via telemetry module 948. Theupdates to the stimulation, sensing, or other programs may be storedwithin stimulation programs 952 or other section of memory 941.Telemetry module 948 in IMD 916, as well as telemetry modules in otherdevices and systems described herein, such as programmer 922, mayaccomplish communication by RF communication and/or inductancetechniques, among other transcutaneous communication techniques. Forexample, telemetry module 948 may communicate with external medicaldevice programmer 922 via proximal inductive interaction of IMD 916 withprogrammer 922. Accordingly, telemetry module 948 may send informationto external programmer 922 on a continuous basis, at periodic intervals,or upon request from IMD 916 or programmer 922. For example, processor940 may transmit sensed signals, biomarker identification information,episodic information, stimulation history information, and/orinformation concerning a profile of a patient's bioelectrical responseto stimulation to programmer 922 via telemetry module 948.

Power source 950 delivers operating power to various components of IMD916. Power source 950 may include a small rechargeable ornon-rechargeable battery and a power generation circuit to produce theoperating power. Recharging may be accomplished through proximalinductive interaction between an external charger and an inductivecharging coil within IMD 916. In various embodiments, traditionalbatteries may be used.

The techniques described in this disclosure, including those attributedto programmer 922, IMD 916, processor, control circuitry or variousconstituent components, may be implemented, at least in part, inhardware, software, firmware or any combination thereof. Such hardware,software, firmware may be implemented within the same device or withinseparate devices to support the various operations and functionsdescribed in this disclosure. While the techniques described herein areprimarily described as being performed by processor 940 of IMD 916and/or processor of a programmer or other external device as part ofcontrol circuitry, any of the one or more parts of the techniquesdescribed herein may be implemented by a processor of one of IMD 916,programmer 922, or another computing device, alone or in combinationwith each other, as control circuitry. For example, the variousfunctional options discussed in connection with FIGS. 1-8 and elsewhereherein can be implemented by a processor (e.g., processor 940) executingprogram instruction stored in memory (e.g., memory 941), as controlcircuitry, that performs the various described functions.

Although the control circuitry of FIG. 10 is generally illustrated anddescribed in terms of an implantable medical device, the controlcircuitry could alternatively be embodied in an at least partiallyexternal device and, depending on the therapy and/or circuitryconfiguration, may be wholly external.

The techniques described in this disclosure, including those discussedin connection with FIGS. 1-8 and those attributed to programmer, IMD,processor, and/or control circuitry, or various constituent components,may be implemented wholly or at least in part, in hardware, software,firmware or any combination thereof. A processor, as used herein, refersto any number and/or combination of a microprocessor, a digital signalprocessor (DSP), an application specific integrated circuit (ASIC), afield-programmable gate array (FPGA), microcontroller, processing chip,gate arrays, and/or any other equivalent integrated or discrete logiccircuitry. “Control circuitry” as used herein refers to at least one ofthe foregoing logic circuitry as a processor, alone or in combinationwith other circuitry, such as memory or other physical medium forstoring instructions, as needed to carry about specified functions(e.g., a processor and memory having stored program instructionsexecutable by the processor as control circuitry configured to carry outone or more specified functions). The functions referenced herein (e.g.,those discussed in connection with FIGS. 1-8) may be embodied asfirmware, hardware, software or any combination thereof as part ofcontrol circuitry specifically configured (e.g., with programming) tocarry out those functions, such as in means for performing the functionsreferenced herein. The steps described herein may be performed by asingle processing component or multiple processing components, thelatter of which may be distributed amongst different coordinatingdevices (e.g., an IMD and an external programmer). In this way, controlcircuitry may be distributed between multiple devices, including animplantable medical device and an external medical device in varioussystems. In addition, any of the described units, modules, or componentsmay be implemented together or separately as discrete but interoperablelogic devices of control circuitry. Depiction of different features asmodules or units is intended to highlight different functional aspectsand does not necessarily imply that such modules or units must berealized by separate hardware or software components and/or by a singledevice. Rather, functionality associated with one or more module orunits, as part of control circuitry, may be performed by separatehardware or software components, or integrated within common or separatehardware or software components of the control circuitry.

When implemented in software, the functionality ascribed to the systems,devices and control circuitry described in this disclosure may beembodied as instructions on a physically embodied computer-readablemedium such as RAM, ROM, NVRAM, EEPROM, FLASH memory, magnetic datastorage media, optical data storage media, or the like, the medium beingphysically embodied in that it is not a carrier wave, as part of controlcircuitry. The instructions may be executed to support one or moreaspects of the functionality described in this disclosure.

It is noted that this disclosure is presented in an exemplary format andnot in a limiting manner. The scope of this disclosure is not limited tothe specific embodiments presented herein. The various options shownherein can be selectively employed and modified by one having ordinaryskill in the art to practice the subject matter of this disclosure.

The invention claimed is:
 1. A method comprising: controllingstimulation circuitry to deliver electrical stimulation to a brain at aplurality of different levels of a stimulation parameter; sensing, usingone or more electrodes, bioelectrical brain activity, wherein sensingthe bioelectrical brain activity of the brain comprises sensing abioelectrical response of the brain to the delivery of the electricalstimulation at each of the plurality of different levels of thestimulation parameter, wherein sensing the bioelectrical responsecomprises sensing an after-discharge episode resulting from the deliveryof the electrical stimulation at at least one level of the plurality ofdifferent levels of the stimulation parameter; identifying a window ofthe stimulation parameter having a first threshold as a lower boundaryand an after-discharge threshold as an upper boundary based on thesensed bioelectrical brain activity, wherein identifying a window of thestimulation parameter based on the sensed biological brain activitycomprises determining the first threshold and the after-dischargethreshold of the window of the stimulation parameter based on the sensedbioelectrical activity, wherein determining the after-dischargethreshold comprises determining the after discharge threshold based onthe at least one level of the plurality of different levels of thestimulation parameter that resulted in the sensed after-dischargeepisode; and setting a therapy level of the stimulation parameter fortherapy delivery to the brain based on the window, wherein sensing,delivering, identifying, and setting are each performed at least in partby control circuitry.
 2. The method of claim 1, wherein the sensing,using the one or more electrodes, the bioelectrical brain activity ofthe brain of the patient comprises periodically sensing, using the oneor more electrodes, the bioelectrical brain activity of the brain of thepatient, and wherein the identifying the window of the stimulationparameter having the first threshold as the lower boundary and theafter-discharge threshold as the upper boundary based on the sensedbioelectrical brain activity comprises periodically identifying theafter-discharge threshold as the upper boundary based on the sensedbioelectrical brain activity such that the upper boundary isperiodically adjusted.
 3. The method of claim 1, wherein the sensing,using the one or more electrodes, the bioelectrical brain activity ofthe brain of the patient comprises continuously sensing, using the oneor more electrodes, the bioelectrical brain activity of the brain of thepatient, and wherein the identifying the window of the stimulationparameter having the first threshold as the lower boundary and theafter-discharge threshold as the upper boundary based on the sensedbioelectrical brain activity comprises continuously identifying theafter-discharge threshold as the upper boundary based on the sensedbioelectrical brain activity such that the upper boundary iscontinuously adjusted.
 4. The method of claim 1, wherein the electricalstimulation comprises a first electrical stimulation, wherein thebioelectrical brain activity comprises a first bioelectrical brainactivity, and wherein the bioelectrical response comprises a firstbioelectrical response, the method further comprising: subsequentlycontrolling the stimulation circuitry to deliver a second electricalstimulation to the brain at the plurality of different levels of thestimulation parameter; sensing, using the one or more electrodes, asecond bioelectrical brain activity, wherein sensing the secondbioelectrical brain activity of the brain comprises sensing a secondbioelectrical response of the brain to the delivery of the secondelectrical stimulation at each of the plurality of different levels ofthe stimulation parameter; and adjusting the after-discharge thresholdas the upper boundary based on the sensed second bioelectrical brainactivity.
 5. The method of claim 1, wherein the first thresholdcomprises a therapeutic effect threshold at which a therapeutic effectis produced by the stimulation.
 6. The method of claim 1, furthercomprising determining a frequency domain characteristic of the sensedbioelectrical brain activity, wherein identifying the window of thestimulation parameter having the first threshold as the lower boundaryand the after-discharge threshold as the upper boundary based on thesensed bioelectrical brain activity comprises identifying the window ofthe stimulation parameter having the first threshold as the lowerboundary and the after-discharge threshold as the upper boundary basedon the determined frequency domain characteristic.
 7. The method ofclaim 6, wherein the frequency domain characteristic of the sensedbioelectrical brain activity comprises at least one of a power level inone or more frequency bands of the sensed bioelectrical brain activityor a ratio of power levels in at least two frequency bands of the sensedbioelectrical brain activity.
 8. The method of claim 1, wherein thesensed bioelectrical brain activity comprises sensed local fieldpotential signals.
 9. The method of claim 1, wherein the first thresholdcomprises a suppression threshold.
 10. The method of claim 1, whereinthe stimulation parameter is a stimulation amplitude.
 11. The method ofclaim 1, further comprising controlling the stimulation circuitry todeliver the therapy to the brain of the patient with the set therapylevel of the stimulation parameter.
 12. The method of claim 1, whereinthe electrical stimulation comprises a first electrical stimulation,wherein the bioelectrical brain activity comprises a first bioelectricalbrain activity, and wherein the bioelectrical response comprises a firstbioelectrical response, the method further comprising: controlling thestimulation circuitry to deliver the therapy to the brain of the patientwith the set therapy level of the stimulation parameter; subsequentlycontrolling the stimulation circuitry to deliver a second electricalstimulation to the brain at the plurality of different levels of thestimulation parameter; sensing, using the one or more electrodes, asecond bioelectrical brain activity, wherein sensing the secondbioelectrical brain activity of the brain comprises sensing a secondbioelectrical response of the brain to the delivery of the secondelectrical stimulation at each of the plurality of different levels ofthe stimulation parameter, wherein sensing the bioelectrical responsecomprises sensing another after-discharge episode resulting from thedelivery of the second electrical stimulation at at least one level ofthe plurality of different levels of the stimulation parameter; andadjusting the after-discharge threshold as the upper boundary of thewindow of the stimulation parameter based on the at least one level ofthe plurality of different levels of the stimulation parameter thatresulted in the sensed another after-discharge episode.
 13. The methodof claim 12, further comprising: resetting the therapy level of thestimulation parameter for therapy delivery to the brain based on theadjusted after-discharge threshold; and controlling the stimulationcircuitry to deliver the therapy to the brain of the patient with thereset therapy level of the stimulation parameter.
 14. A systemcomprising: one or more electrodes; stimulation circuitry configured togenerate electrical stimulation; and control circuitry configured to:control the stimulation circuitry to deliver the electrical stimulationto a brain at a plurality of different levels of a stimulationparameter; sense, using the one or more electrodes, bioelectrical brainactivity, wherein sensing the bioelectrical brain activity of the braincomprises sensing a bioelectrical response of the brain to the deliveryof the electrical stimulation at each of the plurality of differentlevels of the stimulation parameter, wherein the control circuitry isconfigured to sense an after-discharge episode resulting from thedelivery of the electrical stimulation at at least one level of theplurality of different levels of the stimulation parameters; identify awindow of the stimulation parameter having a first threshold as a lowerboundary and an after-discharge threshold as an upper boundary based onthe sensed bioelectrical brain activity, wherein the control circuitryis configured to determine the first threshold and the after-dischargethreshold of the stimulation parameter based on the sensed bioelectricalactivity, wherein the control circuitry is configured to determine theafter discharge threshold based on the at least one level of theplurality of different levels of the stimulation parameter that resultedin the sensed after-discharge episode; and set a level of thestimulation parameter for therapy delivery to the brain based on thewindow.
 15. The system of claim 14, wherein the control circuitry isconfigured to periodically sense, using the one or more electrodes, thebioelectrical brain activity of the brain of the patient, andperiodically identify the after-discharge threshold as the upperboundary based on the sensed bioelectrical brain activity such that theupper boundary is periodically adjusted.
 16. The system of claim 14,wherein the control circuitry is configured to continuously sense, usingthe one or more electrodes, the bioelectrical brain activity of thebrain of the patient, and continuously identify the after-dischargethreshold as the upper boundary based on the sensed bioelectrical brainactivity such that the upper boundary is continuously adjusted.
 17. Thesystem of claim 14, wherein the electrical stimulation comprises a firstelectrical stimulation, wherein the bioelectrical brain activitycomprises a first bioelectrical brain activity, wherein thebioelectrical response comprises a first bioelectrical response, andwherein the control circuitry is configured to: subsequently control thestimulation circuitry to deliver a second electrical stimulation to thebrain at the plurality of different levels of the stimulation parameter;sense, using the one or more electrodes, a second bioelectrical brainactivity, wherein sensing the second bioelectrical brain activity of thebrain comprises sensing a second bioelectrical response of the brain tothe delivery of the second electrical stimulation at each of theplurality of different levels of the stimulation parameter; and adjustthe after-discharge threshold as the upper boundary based on the sensedsecond bioelectrical brain activity.
 18. The system of claim 14, whereinthe first threshold comprises a therapeutic effect threshold at which atherapeutic effect is produced by the stimulation.
 19. The system ofclaim 14, wherein the control circuitry is configured to determine afrequency domain characteristic of the sensed bioelectrical brainactivity, and identify the window of the stimulation parameter havingthe first threshold as the lower boundary and the after-dischargethreshold as the upper boundary based on the determined frequency domaincharacteristic.
 20. The system of claim 19, wherein the frequency domaincharacteristic of the sensed bioelectrical brain activity comprises atleast one of a power level in one or more frequency bands of the sensedbioelectrical brain activity or a ratio of power levels in at least twofrequency bands of the sensed bioelectrical brain activity.
 21. Thesystem of claim 14, wherein the sensed bioelectrical brain activitycomprises sensed local field potential signals.
 22. The system of claim14, wherein the first threshold comprises a suppression threshold. 23.The system of claim 14, wherein the stimulation parameter is astimulation amplitude.
 24. The system of claim 14, wherein the controlcircuitry is configured to control the stimulation circuitry to deliverthe therapy to the brain of the patient with the set therapy level ofthe stimulation parameter.
 25. The system of claim 14, wherein theelectrical stimulation comprises a first electrical stimulation, whereinthe bioelectrical brain activity comprises a first bioelectrical brainactivity, wherein the bioelectrical response comprises a firstbioelectrical response, and wherein the control circuitry is configuredto: control the stimulation circuitry to deliver the therapy to thebrain of the patient with the set therapy level of the stimulationparameter subsequently control the stimulation circuitry to deliver asecond electrical stimulation to the brain at the plurality of differentlevels of the stimulation parameter; sense, using the one or moreelectrodes, a second bioelectrical brain activity, wherein sensing thesecond bioelectrical brain activity of the brain comprises sensing asecond bioelectrical response of the brain to the delivery of the secondelectrical stimulation at each of the plurality of different levels ofthe stimulation parameter, wherein the control circuitry is configuredto sense another after-discharge episode resulting from the delivery ofthe second electrical stimulation at at least one level of the pluralityof different levels of the stimulation parameters; and adjust theafter-discharge threshold as the upper boundary of the window of thestimulation parameter based on the at least one level of the pluralityof different levels of the stimulation parameter that resulted in thesensed another after-discharge episode.
 26. The system of claim 25,wherein the control circuitry is configured to: reset the therapy levelof the stimulation parameter for therapy delivery to the brain based onthe adjusted after-discharge threshold; and control the stimulationcircuitry to deliver the therapy to the brain of the patient with thereset therapy level of the stimulation parameter.